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Vaccines: Correlates of Vaccine‐Induced Immunity
Abstract
The immune system is redundant, and B and T cells collaborate. However, almost all current vaccines work through induction
of antibodies in serum or on mucosa that block infection or interfere with microbial invasion of the bloodstream. To protect,
antibodies must be functional in the sense of neutralization or opsonophagocytosis. Correlates of protection after vaccination
are sometimes absolute quantities but often are relative, such that most infections are prevented at a particular level of
response but some will occur above that level because of a large challenge dose or deficient host factors. There may be >1
correlate of protection for a disease, which we term “cocorrelates.” Either effector or central memory may correlate with
protection. Cell-mediated immunity also may operate as a correlate or cocorrelate of protection against disease, rather than
against infection. In situations where the true correlate of protection is unknown or difficult to measure, surrogate tests
(usually antibody measurements) must suffice as predictors of protection by vaccines. Examples of each circumstance are given.
... The vaccine immunogenicity was evaluated by measuring the serum IgG neutralizing Ab levels against the RBD portion of the spike protein (anti-S), using the IgG II Quant kit (Abbott, Chicago, IL, USA), a chemiluminescent microparticle immunoassay (CIMSA) according to the manufacturer's instructions on an Architect i2000SR/i4000SR platform. This assay has an optimized sensitivity Vaccine efficacy, in terms of protective immunity, is correlated to the presence of neutralizing antibodies (38)(39)(40). In this study, the level of IgG against spike receptor binding domain was used as surrogate markers of neutralizing antibodies because their levels are linearly correlated (41,42) and as it was deeply shown in animal models (43,44). ...
... Confirming this hypothesis, in patients undergoing ruxolitinib treatment, recently, an impaired response to the first (29) and second dose of vaccine (21,47) has been demonstrated. Antibodies elicited by vaccination are of key importance to protect subjects from the disease or, in other words, might be able to neutralize the virus (38). ...
... However, a specific and robust T cell response is more likely to be seen in those patients that elicited a broad functional humoral immune response (50,55). Thus, antibody levels might be used as a surrogate marker of a good immune response, not limited to B-cells, and can be predictive of protection given by vaccination as the true defensive strength is difficult to assess (38,39). ...
Patients affected by myelofibrosis (MF) or polycythemia vera (PV) and treated with ruxolitinib are at high risk for severe coronavirus disease 2019. Now a vaccine against the virus SARS-CoV-2, which is responsible for this disease, is available. However, sensitivity to vaccines is usually lower in these patients. Moreover, fragile patients were not included in large trials investigating the efficacy of vaccines. Thus, little is known about the efficacy of this approach in this group of patients. In this prospective single-center study, we evaluated 43 patients (30 MF patients and 13 with PV) receiving ruxolitinib as a treatment for their myeloproliferative disease. We measured anti-spike and anti-nucleocapsid IgG against SARS-CoV2 15-30 days after the second and the third BNT162b2 mRNA vaccine booster dose. Patients receiving ruxolitinib showed an impaired antibody response to complete vaccination (2 doses), as 32.5% of patients did not develop any response. After the third booster dose with Comirnaty, results slightly improved, as 80% of these patients produced antibodies above the threshold positivity. However, the quantity of produced antibodies was well below that reached than those reported for healthy individuals. PV patients elicited a better response than patients affected by MF. Thus, different strategies should be considered for this high-risk group of patients.
... Some CoPs are mechanistic (i.e. directly responsible for protection), while others are non-mechanistic or surrogate, and although not directly responsible for protection, can be used in substitute of the true correlate [3,4]. A CoP can be absolute, where protection against disease is certain above a threshold, or relative, where higher levels of a biomarker correspond to more protection [2]. ...
... These findings echo SARS-CoV-2 vaccine trial data showing protection after one dose with very low levels of neutralizing antibodies, and suggest that cellular immunity or non-neutralizing antibodies may also play a role in protection [31,41]. Our review of the literature indicates that a humoral SARS-CoV-2 CoP may be relative, such that antibodies reduce risk of infection but not eliminated it [4]. An analogous example is the influenza 50% protective dose, defined as the antibody concentration at which the risk of infection is reduced by half [3,42]. ...
Background
A correlate of protection (CoP) is an immunological marker associated with protection against infection. Despite an urgent need, a CoP for SARS-CoV-2 is currently undefined.
Objectives
Our objective was to review the evidence for a humoral correlate of protection for SARS-CoV-2, including variants of concern.
Methods
We searched OVID MEDLINE, EMBASE, Global Health, Biosis Previews and Scopus to January 4, 2022 and pre-prints (using NIH iSearch COVID-19 portfolio) to December 31, 2021, for studies describing SARS-CoV-2 re-infection or breakthrough infection with associated antibody measures. Two reviewers independently extracted study data and performed quality assessment.
Results
Twenty-five studies were included in our systematic review. Two studies examined the correlation of antibody levels to VE, and reported values from 48.5% to 94.2%. Similarly, several studies found an inverse relationship between antibody levels and infection incidence, risk, or viral load, suggesting that both humoral immunity and other immune components contribute to protection. However, individual level data suggest infection can still occur in the presence of high levels of antibodies. Two studies estimated a quantitative CoP: for Ancestral SARS-CoV-2, these included 154 (95% confidence interval (CI) 42, 559) anti-S binding antibody units/mL (BAU/mL), and 28.6% (95% CI 19.2, 29.2%) of the mean convalescent antibody level following infection. One study reported a CoP for the Alpha (B.1.1.7) variant of concern of 171 (95% CI 57, 519) BAU/mL. No studies have yet reported an Omicron-specific CoP.
Conclusions
Our review suggests that a SARS-CoV-2 CoP is likely relative, where higher antibody levels decrease the risk of infection, but do not eliminate it completely. More work is urgently needed in this area to establish a SARS-CoV-2 CoP and guide policy as the pandemic continues.
... Third, the COVID-19 and control groups were well-matched for age and sex. This is important because age and sex determine immune responses to many vaccines (37,38). Accordingly, differences in vaccine responses observed in the 2 groups in this study are not explainable by differences in age or sex. ...
... First, while our data over 56 days after first injection suggest that spike IgG antibody levels may fall more slowly in the COVID-19 group than in infection-naive individuals, the long-term IgG antibody level was not defined in this study. This is of importance because vaccine protection depends on the sustained antibody level (38). Additional time points will be needed in this regard. ...
Background:
Most subjects with prior COVID-19 disease manifest long-term, protective immune responses against re-infection. Accordingly, we tested the hypothesis that humoral immune and reactogenicity responses to a SARS-CoV-2 mRNA vaccine differ in subjects with and without prior COVID-19.
Methods:
Health care workers (n=61) with (n=30) and without (n=31) prior COVID-19 disease received two, 30 µg doses of Pfizer BNT162b2 vaccine 3 weeks apart. Serum IgG antibody against the Spike receptor-binding domain (RBD); serum neutralizing activity; and vaccine reactogenicity were assessed longitudinally every 2 weeks for 56 days after the 1st injection.
Results:
The COVID group manifested more rapid increases in Spike IgG antibody and serum neutralizing activity post 1st vaccine dose but showed little or no increase after the 2nd dose compared to the infection-naïve group. In fact, Spike IgG was maximum after the 1st dose in 36% of the COVID group versus 0% of the infection-naïve group. Peak IgG antibody was lower but appeared to fall more slowly in the COVID-19 versus the infection-naïve group. Finally, adverse systemic reactions e.g., fever, headache and malaise, were more frequent and lasted longer after both the 1st and 2nd injection in the COVID group than in the infection-naïve group.
Conclusion:
Subjects with prior COVID-19 demonstrate a robust, accelerated humoral immune response to the 1st dose but attenuated response to the 2nd dose of BNT162b2 vaccine compared to controls. The COVID-19 group also experiences greater reactogenicity. Humoral responses and reactogenicity to BNT162b2 differ qualitatively and quantitatively in subjects with prior COVID-19 compared to infection-naive subjects.
Funding:
This work was supported by Institutional Funds.
... Accordingly, possibly a more accurate predictor of NA as a CoP is combining serum NA with anti-PRRSV IgA in the respiratory tract (nasal or oral fluids). Plotkin described this CoP for influenza because like PRRSV, influenza infects cells in the mucosa (epithelial cells not alveolar macrophages) [138]. He described the role of IgG and IgA as synergistic CoP with both being responsible for a significant drop in viral shedding compared to either individually. ...
Porcine reproductive and respiratory syndrome virus (PRRSV) is an on-going problem for the worldwide pig industry. Commercial and experimental vaccinations often demonstrate reduced pathology and improved growth performance; however, specific immune correlates of protection (CoP) for PRRSV vaccination have not been quantified or even definitively postulated: proposing CoP for evaluation during vaccination and challenge studies will benefit our collective efforts towards achieving protective immunity. Applying the breadth of work on human diseases and CoP to PRRSV research, we advocate four hypotheses for peer review and evaluation as appropriate testable CoP: (i) effective class-switching to systemic IgG and mucosal IgA neutralizing antibodies is required for protective immunity; (ii) vaccination should induce virus-specific peripheral blood CD4+ T-cell proliferation and IFN-γ production with central memory and effector memory phenotypes; cytotoxic T-lymphocytes (CTL) proliferation and IFN-γ production with a CCR7- phenotype that should migrate to the lung; (iii) nursery, finishing, and adult pigs will have different CoP; (iv) neutralizing antibodies provide protection and are rather strain specific; T cells confer disease prevention/reduction and possess greater heterologous recognition. We believe proposing these four CoP for PRRSV can direct future vaccine design and improve vaccine candidate evaluation.
... An important contribution to the protection provided by the adaptive immune response is the generation of antibodies, which is a typical consequence of infection and a key aim of vaccination. 1 Antibodies can be generated through two predominant, interconnected pathways. In primary responses, extrafollicular (EF) responses, which develop in the red pulp of the spleen or the medulla in lymph nodes, provide the first wave of IgM and IgG, and these antibodies are typically of modest affinity because there is limited affinity maturation of B cells that enter this pathway. ...
Germinal centers (GCs) are sites where plasma and memory B cells form to generate high-affinity, Ig class-switched antibodies. Specialized stromal cells called follicular dendritic cells (FDCs) are essential for GC formation. During systemic Salmonella Typhimurium (STm) infection GCs are absent, whereas extensive extrafollicular and switched antibody responses are maintained. The mechanisms that underpin the absence of GC formation are incompletely understood. Here, we demonstrate that STm induces a reversible disruption of niches within the splenic microenvironment, including the T and B cell compartments and the marginal zone. Alongside these effects after infection, mature FDC networks are strikingly absent, whereas immature FDC precursors, including marginal sinus pre-FDCs (MadCAM-1+) and perivascular pre-FDCs (PDGFRβ+) are enriched. As normal FDC networks re-establish, extensive GCs become detectable throughout the spleen. Therefore, the reorganization of FDC networks and the loss of GC responses are key, parallel features of systemic STm infections.
... Serum is generally considered the "gold standard" sample to measure protective immunity [33]. DBS samples offer an attractive alternative to serum antibody testing, and our experiments with DBS made from anti GBS IgG positive serum reconstituted with red blood cells have shown that there is no significant differences between serum and DBS, as has been seen in other studies [34,35]. ...
Vaccination during pregnancy could protect women and their infants from invasive Group B Streptococcus (GBS) disease. To understand if neonatal dried blood spots (DBS) can be used to determine the amount of maternally derived antibody that protects infants against invasive GBS disease, a retrospective case-control study was conducted in England between 1 April 2014 and 30 April 2015. The DBS of cases with invasive GBS disease (n = 61) were matched with healthy controls (n = 125). The haematocrit, DBS storage temperature, freeze-thaw cycle, and paired serum/DBS studies were set up to optimise the antibody assessment. The samples were analysed using a multiplex immunoassay, and the results were assessed using parametric and nonparametric tests. Antibody concentrations were stable at haematocrits of up to 50% but declined at 75%. DBS storage at room temperature was stable for three months compared with storage from collection at −20 °C and rapidly degraded thereafter. Total IgG levels measured in DBS and paired serum showed a good correlation (r2 = 0.99). However, due to suboptimal storage conditions, no difference was found in the GBS IgG levels between DBS samples from cases and controls. We have demonstrated a proof of concept that assays utilising DBS for assessing GBS serotype-specific antibodies in infants is viable. This method could be used to facilitate future large sero-correlate studies, but DBS samples must be stored at −20 °C for long term preservation of antibody.
... There is general consensus that generating enough antibodies to block infection is a key challenge for induction protection in malaria vaccines [31]. Another recently discovered hurdle is epitope masking as an obstacle to antibody boosting after repeated administration of the attenuated P. falciparum sporozoite vaccine [32]. ...
Malaria is a parasitic infection that is a great public health concern and is responsible for high mortality rates worldwide. Different strategies have been employed to improve disease control, demonstrating the ineffectiveness of controlling vectors, and parasite resistance to antimalarial drugs requires the development of an effective preventive vaccine. There are countless challenges to the development of such a vaccine directly related to the parasite’s complex life cycle. After more than four decades of basic research and clinical trials, the World Health Organization (WHO) has recommended the pre-erythrocytic Plasmodium falciparum (RTS, S) malaria vaccine for widespread use among children living in malaria-endemic areas. However, there is a consensus that major improvements are needed to develop a vaccine with a greater epidemiological impact in endemic areas. This review discusses novel strategies for malaria vaccine design taking the target stages within the parasite cycle into account. The design of the multi-component vaccine shows considerable potential, especially as it involves transmission-blocking vaccines (TBVs) that eliminate the parasite’s replication towards sporozoite stage parasites during a blood meal of female anopheline mosquitoes. Significant improvements have been made but additional efforts to achieve an efficient vaccine are required to improve control measures. Different strategies have been employed, thus demonstrating the ineffectiveness in controlling vectors, and parasite resistance to antimalarial drugs requires the development of a preventive vaccine. Despite having a vaccine in an advanced stage of development, such as the RTS, S malaria vaccine, the search for an effective vaccine against malaria is far from over. This review discusses novel strategies for malaria vaccine design taking into account the target stages within the parasite’s life cycle.
... In vitro neutralizing antibody titers against SARS-CoV-2 present a clear correlate of protection from symptomatic SARS-CoV-2 infection. Studies of passive administration of neutralizing monoclonal antibodies in animals and humans support that neutralizing antibody titers are a mechanistic correlate of protection (21)(22)(23). Indeed, a recent study comparing protective titers in prophylactic and therapeutic studies suggests that the protective titers may be very similar (E. ...
Several studies have shown that neutralizing antibody levels correlate with immune protection from COVID-19 and have estimated the relationship between neutralizing antibodies and protection. However, results of these studies vary in terms of estimates of the level of neutralizing antibodies required for protection. By normalizing antibody titers, we found that study results converge on a consistent relationship between antibody levels and protection from COVID-19. This finding can be useful for planning future vaccine use, determining population immunity, and reducing the global effects of the COVID-19 pandemic.
... A correlate of protection (CoP) is an immune function that correlates with and may be biologically responsible for vaccine-induced efficacy. The literature on this subject has grown considerably since it was identified as an important issue in vaccinology (1)(2)(3)(4)(5). The importance of CoP with regard to vaccines against SARS-2, the coronavirus causing COVID-19, needs no emphasis, and numerous papers have been published on that subject (6). ...
Correlates of protection are key for vaccine development against any pathogen. In this paper we summarize recent information about correlates for vaccines against dengue, Ebola, influenza, pneumococcal, respiratory syncytial virus, rotavirus, shigella, tuberculosis and Zika virus.
... There is general consensus that generating enough antibodies to block infection is a key challenge for induction protection in malaria vaccines [30]. Another recently discovered hurdle is epitope masking as an obstacle to antibody boosting after repeated administration of the attenuated P. falciparum sporozoite vaccine [31]. ...
Malaria is a parasitic infection that is a great public health concern and is responsible for high mortality rates worldwide. Different strategies have been employed to improve disease control, demonstrating the ineffectiveness of controlling vectors, and parasite resistance to antimalarial drugs requires the development of an effective preventive vaccine. There are countless challenges to the development of such a vaccine directly related to the parasite's complex life cycle. After more than four decades of basic research and clinical trials, the World Health Organization (WHO) has recommended the pre-erythrocytic Plasmodium falciparum (RTS, S) malaria vaccine for widespread use among children living in malaria-endemic areas. However, there is a consensus that major improvements are needed to develop a vaccine with a greater epidemiological impact in endemic areas. This review discusses novel strategies for malaria vaccine design taking the target stages within the parasite cycle into account. The design of the multi-component vaccine shows considerable potential, especially as it involves transmission-blocking vaccines (TBVs) that eliminate the parasite's replication towards sporozoite stage parasites during a blood meal of female anopheline mosquitoes. Significant improvements have been made but additional efforts to achieve an efficient vaccine are required to improve control measures. Different strategies have been employed, thus demonstrating the ineffectiveness in controlling vectors, and parasite resistance to antimalarial drugs requires the development of a preventive vaccine. Despite having a vaccine in an advanced stage of development, such as the RTS, S malaria vaccine, the search for an effective vaccine against malaria is far from over. This review discusses novel strategies for malaria vaccine design taking into account the target stages within the parasite’s life cycle.
... Presence above antibody cut-off levels can in some contexts infer protection, although how much such levels correlate with protection, varies on a range of factors. 2,3 Nonetheless, community-based serological surveillance is an important tool to augment understanding of population level immunity achieved through vaccine coverage over many years and/or immunity to VPDs derived from prior infection. 4 The results of serosurveys can be used to guide supplementary immunisation activities (SIAs), and tailor routine immunisation service delivery. ...
Introduction: Historic disruption in health infrastructure combined with data from a recent vaccine coverage survey suggests there are likely significant immunity gaps to vaccine preventable diseases and high risk of outbreaks in Timor-Leste. Community-based serological surveillance is an important tool to augment understanding of population-level immunity achieved through vaccine coverage and/or derived from prior infection.
Methods and analysis: This national population-representative serosurvey will take a three-stage cluster sample and aims to include 5600 individuals above one year of age. Serum samples will be collected by phlebotomy and analysed for measles immunoglobulin G (IgG), rubella IgG, severe acute respiratory syndrome coronavirus-2 anti-spike protein IgG, hepatitis B surface antibody and hepatitis B core antigen using commercially available chemiluminescent immunoassays or enzyme-linked immunosorbent assays. In addition to crude prevalence estimates and to account for differences in Timor-Leste age structure, we will calculate stratified age-standardised prevalence estimates, using Asia in 2013 as the standard population. Additionally, this survey will derive a national asset of serum and dried blood spot samples which can be used for further investigation of infectious disease sero-epidemiology and/or validation of existing and novel serological assays for infectious diseases.
Ethics and dissemination: Ethical approval has been obtained from the Research Ethics and Technical Committee of the Instituto Nacional da Saude,Timor-Leste and the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research, Australia. Co-designing this study with Timor-Leste Ministry-of-Health and other relevant partner organisations will allow immediate translation of findings into public health policy (which may include changes to routine immunisation service delivery and/or plans for supplementary immunisation activities).
... While nAbs in those immunized long ago were detectable decades later, a protective threshold has not been defined for smallpox, monkeypox, or other orthopox viruses [37]. At booster study baseline, those who received primary MVA-BN immunizations 2 years earlier exhibited nAb levels that had declined to near baseline levels. ...
Background
Though Modified Vaccinia Ankara - Bavarian Nordic (MVA-BN®). vaccination is approved for smallpox and monkeypox prevention, immunological persistence and booster effects remain undescribed.
Methods
Participants naïve to smallpox vaccination were randomized to 1 dose MVA-BN (1×MVA, N = 181), 2 doses MVA-BN (2×MVA, N = 183), or placebo (N = 181). Participants with previous smallpox vaccination received 1 MVA-BN booster (HSPX+, N = 200). Subsets of the formerly naïve groups (∼75 each) received an MVA-BN booster 2 years later.
Results
Neutralizing antibody (nAb) geometric mean titers (GMTs) increased from 1.1 (baseline, both naïve groups) to 7.2 and 7.5 (Week 4, 1×MVA and 2×MVA, respectively), and further to 45.6 (Week 6, 2×MVA after second vaccination). In HSPX+, nAb GMT rapidly increased from 21.6 (baseline) to 175.1 (Week 2). At 2 years, GMTs for 1×MVA, 2×MVA, and HSPX+ were 1.1, 1.3, and 10.3, respectively. After boosting in the previously naïve groups, nAb GMTs increased rapidly in 2 weeks to 80.7 (1×MVA) and 125.3 (2×MVA), higher than after primary vaccination and comparable to boosted HSPX+ subjects. Six months after boosting, GMTs were 25.6 (1×MVA) and 49.3 (2×MVA). No safety concerns were identified.
Conclusion
Anamnestic responses without sustained high nAb titers support presence of durable immunological memory following MVA-BN immunization.
... Identifying the correlations of protective immunity is important, and the best and most often-de ned correlate of protection in almost any respiratory infectious illness to date has been antibodies 29 . Antibodies have been shown to neutralize infectivity by attaching to viral surface proteins and trigger complement activation to provide antibody-dependent, cell-mediated cytotoxicity against infected viruses and cells. ...
Longitudinal serum samples, nasopharyngeal/nasal swabs and rectal swab samples were collected from eighty-nine individuals (median age 66 y) with SARS-CoV-2 PCR-positive test results at Linköping University Hospital. Samples were collected from the initial visit and thereafter for up to 2 years of follow-up. The presence of serum IgG and IgA against SARS-CoV-2 antigens (S1-spike, nucleocapsid, and NSP3) was analysed. Nasal and rectal swabs were tested for the presence of mucosal IgA against the outer envelope S1 spike and the nucleocapsid protein.
Ninety percent of the participants were seropositive for SARS-CoV-2 recombinant proteins on Day 28 after study entry, and all (100%) were seropositive based on samples collected 2 months or later. Almost all (95%) developed serum SARS-CoV-2-neutralizing antibodies that were measurable from 6 to 24 months. The most common antibody responses (both serum IgG, mainly IgG1, and in nasal mucosa IgA) reacted with the S1-spike protein and the nucleoprotein. In samples collected from nasal tissues, IgA anti-S1 spike protein was mainly observed during 2 months of follow-up. In a subpopulation (18% of tested individuals), rectal IgA swabs showed the presence of anti-S1 spike IgA for 1 month of follow-up among the participants studied.
.
... The copyright holder for this preprint this version posted September 9, 2022. ; lived B-cell memory strongly supports protection in the absence of persisting neutralizing antibodies, particularly for diseases like smallpox, with longer incubation periods [45]. ...
While the MVA-BN vaccine has been proven protective against smallpox and monkeypox, the long-term immunological persistence or booster effect has not been described. In this set of clinical studies, participants who had never been immunized against smallpox were randomized to receive, 4 weeks apart: 2 placebo vaccinations (PBO group, N =181); 1 MVA-BN vaccination followed by placebo(1×MVA group, N =181); or 2 MVA-BN vaccinations (2×MVA group, N = 183). In addition, participants with a history of smallpox vaccination received 1 MVA-BN booster (HSPX ⁺ group, N = 200). The 1×MVA and 2×MVA groups responded with increases in neutralizing antibody (nAb) GMTs at Week 2 (5.1 and 4.8, respectively) that further increased at Week 4 (7.2 and 7.5). Two weeks after the second primary vaccination in the 2×MVA group (at Week 6), nAb GMT peaked (45.6) before stabilizing 2 weeks thereafter (at Week 8) (34.0). In the HSPX ⁺ group, a rapid anamnestic response was observed with a peak nAb GMT at Week 2 (175.1) that was much larger than the peak responses in either of the primary vaccination (1× or 2×MVA) dose groups of smallpox vaccine-naïve subjects. Persistence of nAbs relative to baseline was observed at 6 months in all groups (highest in HSPX ⁺ ), with a return to near baseline nAb levels 2 years later. Subsets of ∼75 participants each, who received primary vaccinations in the 1×MVA and 2×MVA groups, were administered an MVA-BN booster 2 years later. Both booster dose (BD) groups exhibited rapid anamnestic responses with nAb GMTs that peaked 2 weeks post-booster (80.7 and 125.3). These post-booster titers in the 1×MVA and 2×MVA groups were higher than those observed at any timepoint following primary vaccination, were comparable to HSPX ⁺ subjects who had been administered a booster, and remained elevated at 6 months post-booster (25.6 and 49.3). The observed anamnestic responses, in the absence of sustained detectable nAbs, support the presence of durable immunological memory following MVA-BN immunization. No safety concerns were identified, and the most common adverse event following the 2-year MVA-BN booster was injection site erythema in 82.2% of participants.
Clinical Trial Registry Numbers
NCT00316524 and NCT00686582
Highlights
MVA-BN booster-induced anamnestic responses support durable immune memory
One or two primary MVA-BN vaccinations induce similar durable B cell memory responses
Anamnestic responses were observed in those immunized with MVA-BN 2 years earlier
No safety concerns were revealed following a 2-year MVA-BN booster
... However, IgG production takes a longer time to be produced and could be evidence of post-infection immunity even in asymptomatic cases (5). The investigation of post-infection immunity is identified by the functional correlates of protection and defined by endpoints such as the prevention of disease, hospitalization, and death (6). Post-infection immunity against SARS-CoV-2 infection occurred in most people, and reinfection with SARS-CoV-2 was rarely reported and mostly happened in subjects who experienced mild or asymptomatic primary infections (7,8). ...
Aim: Seroprevalence among health care workers (HCWs) has been estimated in different studies in various regions and countries. This study aimed to screen the immunoglobulin M (IgM) and IgG seroprevalences and to assess the durability of IgG seropositivity, as well as the incidence of subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a group of Iranian HCWs. Methods: This voluntary serological screening was prospectively performed on 800 HCWs (492 females and 308 males) in Hamadan between November 2020 and February 2021. Anti-SARS-CoV-2 IgG and IgM antibodies were assessed by the enzyme-linked immunosorbent assay method at two-time intervals. Results: Overall, 243 out of 800 (30.38%) and 66 (8.25%) cases were IgG and IgM seropositive at their first antibody assessment, respectively. The male staff had a higher seroprevalence than females (31.49% vs. 29.67% for IgG, P=0.59 and 10.39% vs. 6.91% for IgM, P=0.08). Higher prevalences for both antibodies were found in the age group of 30-39.9 years (P=0.12 and P=0.05, respectively). In the second antibody screening, 81 (56.6%) cases were IgG seropositive. The mean titer of the first IgG antibody assessment in seropositive cases was lower than that of the second titer (2.95±2.07 vs. 5.08±4.01 cut-off index (COI) , P=1.4×10-5 ). Moreover, the comparison of the first and second IgG titers among 81 seropositive cases demonstrated a significantly increased level of anti-SARS-CoV-2 antibody (5.08±4.01 vs. 3.49±2.41 COI, P=0.002). Conclusions: Our findings revealed that the mean level of the anti-SARS-CoV-2 IgG antibody was significantly increased in the seropositive individuals after 2 months of follow-up.
... IFN-γ released by CD4+ T cells is considered to play an important role in vaccine response. [5] Teijaro et al. observed increased type 1 interferon response after m-RNA vaccines and vector vaccines. [6] It is also known that there is an increased type 1 interferon response in patients with vitiligo. ...
... Correlation between vaccine-induced immunity through vaccination methods for protection in the body. Through the induction of antibodies in serum or mucus that block infection or interfere with the invasion of the body's microbes [16]. Adaptive responses related to protection, such as whether the response will have maximum effect or not because not all vaccine correlations work to treat infections [17]. ...
For two years, people in the world are still battling an outbreak caused by the covid-19 virus that continues to mutate. Health is an important thing that must always be considered to maintain the body's defenses from current viral attacks. Vaccination is one of the results of efforts by doctors to reduce the danger caused by the virus to the body. However, there are still many people who doubt the usefulness of vaccines. They think the vaccine will damage the body because it puts bacteria into it. Through this paper, the authors put efforts to analyze the correlation between immunity and vaccines through vaccination methods. The author will review verses related to scientific signals related to the topic of discussion in the view of scientific interpretation of Zaghlul an Najar's work in Al Ayat Al Kawniyah Fi Tafsir Alquran Al Karim to support the analysis.
... Vaccine efficacy has been linked to markers of immunological response known as correlates of protection (COP) in many infectious diseases, most commonly neutralising antibody titres [11][12][13][14] . However, host defence against the viral infection involves many constituents of the immune system acting synergistically and dynamically, rather than merely reflected by antibody neutralisation 15,16 . ...
We present an interim analysis of a registered clinical study (NCT04800133) to establish immunobridging with various antibody and cellular immunity markers and to compare the immunogenicity and reactogenicity of 2-dose BNT162b2 and CoronaVac in healthy adolescents as primary objectives. One-dose BNT162b2, recommended in some localities for risk reduction of myocarditis, is also assessed. Antibodies and T cell immune responses are non-inferior or similar in adolescents receiving 2 doses of BNT162b2 (BB, N = 116) and CoronaVac (CC, N = 123) versus adults after 2 doses of the same vaccine (BB, N = 147; CC, N = 141) but not in adolescents after 1-dose BNT162b2 (B, N = 116). CC induces SARS-CoV-2 N and N C-terminal domain seropositivity in a higher proportion of adolescents than adults. Adverse reactions are mostly mild for both vaccines and more frequent for BNT162b2. We find higher S, neutralising, avidity and Fc receptor-binding antibody responses in adolescents receiving BB than CC, and a similar induction of strong S-specific T cells by the 2 vaccines, in addition to N- and M-specific T cells induced by CoronaVac but not BNT162b2, possibly implying differential durability and cross-variant protection by BNT162b2 and CoronaVac, the 2 most used SARS-CoV-2 vaccines worldwide. Our results support the use of both vaccines in adolescents. There are adverse events associated with COVID-19 vaccines, such as myocarditis for adolescents following receipt of SARS-CoV-2 mRNA vaccines. Here the authors compare the immunogenicity and reactogenicity of two widely available SARS-CoV-2 vaccines (BNT162b2, an mRNA vaccine, and CoronaVac, a whole-virus inactivated vaccine) in healthy adolescents.
... However, despite considerable efforts, vaccine development has proven difficult for some infections. For many of the vaccines, the best correlate of protection is humoral immune responses, derived from long-lived B cell memory, in the form of antibody-secreting plasma cells (ASCs) and memory B cells (MBCs) (1). ...
Long-term protective immunity to infectious disease depends on cell-mediated and humoral immune responses. Induction of a strong humoral response relies on efficient B cell activation and differentiation to long-lived plasma cells and memory B cells. For many viral or bacterial infections, a single encounter is sufficient to induce such responses. In malaria, the induction of long-term immunity can take years of pathogen exposure to develop, if it occurs at all. This repeated pathogen exposure and suboptimal immune response coincide with the expansion of a subset of B cells, often termed atypical memory B cells. This subset is present at low levels in healthy individuals as well but it is observed to expand in an inflammatory context during acute and chronic infection, autoimmune diseases or certain immunodeficiencies. Therefore, it has been proposed that this subset is exhausted, dysfunctional, or potentially autoreactive, but its actual role has remained elusive. Recent reports have provided new information regarding both heterogeneity and expansion of these cells, in addition to indications on their potential role during normal immune responses to infection or vaccination. These new insights encourage us to rethink how and why they are generated and better understand their role in our complex immune system. In this review, we will focus on recent advances in our understanding of these enigmatic cells and highlight the remaining gaps that need to be filled.
... Furthermore, in agreement with our findings, these previous studies similarly conclude that SARS-CoV-2 antibody production after Sinopharm vaccination was decreased with increasing age. Older people are more likely to be hospitalized or die from COVID-19 (26) and there is increased evidence that vaccination boosters help to increase antibody levels in the high-risk groups, such as older people (27). ...
Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 emerged in China in 2019 and has since travelled the world infecting millions. SARS-CoV-2 causes Corona Virus Disease (COVID-19), that has to date taken over 4 million lives. The Kingdom of Bahrain’s vaccine roll-out has consisted of Sinopharm’s BBIBP-CorV (Sinopharm) and Pfizer/ BioNtech’s BNT162b2 (Pfizer/BioNtech). Testing for SARS-CoV-2 anti-Spike (S) antibodies is a useful technique in estimating an individual’s immune protection against the infection. In this study we evaluated S antibody levels by electro-chemiluminescence immunoassay in 379 individuals double vaccinated with Sinopharm and 15 of whom were given a booster with the Pfizer/BioNtech vaccine. Among our double vaccinated cohort, we found a spectrum of S antibody levels. Indeed, we found that a significant proportion of individuals with low S antibody levels had clinical conditions, which were mainly immune- related disorders. Furthermore, a significant proportion of individuals with low S antibody levels were above 50 years of age. Finally, we observed a significant increase in S antibody levels after the Pfizer/BioNtech booster was administered. These findings reveal that while a large proportion of Sinopharm vaccinated individuals did not develop high levels of antibodies against the S protein, a booster dose of the Pfizer/BioNtech vaccine significantly enhances S antibody levels, revealing this “triple dose” vaccination strategy as a useful method of ensuring protective immunity against SARS-CoV-2.
... The immunological correlates of protection against SARS-CoV-2 infection are still unknown, where the term "correlate of protection" refers to a laboratory parameter associated with protection from a clinical disease [33]. A coordinated action of CD4 + T cells, CD8 + T cells, and neutralizing antibodies seems necessary to control SARS-CoV-2 infection. ...
Several vaccine strategies are now available to fight the current SARS-CoV-2 pandemic. Those based on the administration of lipid-complexed messenger(m)RNA molecules represent the last frontiers in terms of technology innovation. mRNA molecules coding for the SARS-CoV-2 Spike protein are intramuscularly injected, thereby entering cells by virtue of their encapsulation into synthetic lipid nanovesicles. mRNA-targeted cells express the Spike protein on their plasma membrane in a way that it can be sensed by the immune system, which reacts generating anti-Spike antibodies. Although this class of vaccines appears as the most effective against SARS-CoV-2 infection and disease, their safety and efficiency are challenged by several factors included, but not limited to the following: emergence of viral variants, lack of adequate pharmacokinetics/pharmacodynamics studies, inability to protect oral mucosa from infection, and antibody waning. Emergence of viral variants can be a consequence of mass vaccination carried out in a pandemic time using suboptimal vaccines against an RNA virus. On the other hand, understanding the remainder flaws could be of some help in designing next generation anti-SARS-CoV-2 vaccines. In this commentary, issues regarding the fate of injected mRNA, the tissue distribution of the induced antiviral antibodies, and the generation of memory B cells are discussed. Careful evaluation of both experimental and clinical observations on these key aspects should be taken into account before planning booster administration, vaccination to non-at-risk population, and social restrictions.
... Successful vaccines rely upon the induction of robust B cell responses (1). These responses vary according to the cell fate that a B cell adopts following activation. ...
Upon encountering cognate antigen, B cells can differentiate into short-lived plasmablasts, early memory B cells or germinal center B cells. The factors that determine this fate decision are unclear. Past studies have addressed the role of B cell receptor affinity in this process, but the interplay with other cellular compartments for fate determination is less well understood. Moreover, B cell fate decisions have primarily been studied using model antigens rather than complex pathogen systems, which potentially ignore multifaceted interactions from other cells subsets during infection. Here we address this question using a Plasmodium infection model, examining the response of B cells specific for the immunodominant circumsporozoite protein (CSP). We show that B cell fate is determined in part by the organ environment in which priming occurs, with the majority of the CSP-specific B cell response being derived from splenic plasmablasts. This plasmablast response could occur independent of T cell help, though gamma-delta T cells were required to help with the early isotype switching from IgM to IgG. Interestingly, selective ablation of CD11c+ dendritic cells and macrophages significantly reduced the splenic plasmablast response in a manner independent of the presence of CD4 T cell help. Conversely, immunization approaches that targeted CSP-antigen to dendritic cells enhanced the magnitude of the plasmablast response. Altogether, these data indicate that the early CSP-specific response is predominately primed within the spleen and the plasmablast fate of CSP-specific B cells is driven by macrophages and CD11c+ dendritic cells.
... Developing an effective HIV-1 vaccine remains a top priority. In general, all vaccines work by generating Abs that block infection or interfere with viral replication (1). In the case of HIV-1, neutralizing Abs (nAbs) are insufficient to prevent infection. ...
Background:
HIV-1 vaccine efforts are primarily directed towards eliciting neutralizing antibodies (nAbs). However, vaccine trials and mother to child natural history cohort investigations indicate that antibody-dependent cellular cytotoxicity (ADCC), not nAbs, correlate with prevention. The ADCC characteristics associated with lack of HIV-1 acquisition remain unclear.
Methods:
Here we examine ADCC and nAb properties in pre-transmission plasma from HIV-1 exposed infants and from the corresponding transmitting and non-transmitting mothers' breast milk and plasma. Breadth and potency (BP) is assessed against a panel of heterologous, non-maternal, variants. ADCC and neutralization sensitivity is estimated for the strains present in the infected mothers.
Results:
Infants that eventually acquire HIV-1 and those that remain uninfected have similar pre-transmission ADCC BP. The viruses circulating in the transmitting and the non-transmitting mothers also have similar ADCC susceptibility. Infants with a combination of higher pre-transmission ADCC BP and exposure to more ADCC susceptible strains are less likely to acquire HIV-1. In contrast, higher pre-existing infant neutralization BP and greater maternal virus neutralization sensitivity does not associate with transmission. Infants have higher ADCC BP closer to birth and in the presence of high plasma IgG relative to IgA levels. Mothers with potent humoral responses against their autologous viruses harbor more ADCC sensitive strains.
Conclusion:
ADCC sensitivity of the exposure variants along with preexisting ADCC BP influence mother to child HIV-1 transmission during breastfeeding. Vaccination strategies that enhance ADCC responses are likely not sufficient to prevent HIV-1 transmission because strains present in chronically infected individuals can have low ADCC susceptibility.
Trial registration:
NCT00164736 for BAN study.
... 10 109 Vaccine efficacy has been linked to markers of immunological response known as 110 correlates of protection (COP) in many infectious diseases, including neutralizing antibody titres 111 and levels of spike protein (S) IgG for symptomatic COVID-19. [11][12][13][14] However, host defence 112 against the viral infection involves many constituents of the immune system acting 113 synergistically and dynamically, rather than merely reflected by antibody neutralization or S 114 IgG. 15,16 As examples, non-neutralizing binding antibodies may play a role in protecting against . ...
For SARS-CoV-2 vaccines, efficacy data for BNT162b2 but not CoronaVac are available in adolescents. Phase II/III studies focused on neutralizing antibody responses in adolescents, neglecting binding antibody and cellular responses that are also important against SARS-CoV-2. Therefore, we conducted a registered clinical study (NCT04800133) to establish immunobridging with various antibody and cellular immunity markers and to compare the immunogenicity and reactogenicity of these 2 vaccines in healthy adolescents. One-dose BNT162b2 outcomes were also assessed since it had been recommended in some localities due to the risk of myocarditis. Antibodies and T cell immune responses were non-inferior or similar in adolescents receiving 2 doses of BNT162b2 (BB, N=116) and CoronaVac (CC, N=123) versus adults after 2 doses of the same vaccine (BB, N=147; CC, N=141) but not in adolescents after 1 dose of BNT162b2 (B, N=116). CC induced SARS-CoV-2 nucleocapsid (N) and N C-terminal domain seroconversion in more adolescents than adults. Adverse reactions were mostly mild for both vaccines and more frequent for BNT162b2. We confirmed higher S, neutralizing, avidity and Fc receptor-binding antibody responses in adolescents receiving BB than CC. This is the first study to show similar induction of strong S-specific T cells by the 2 vaccines, in addition to N- and M-specific T cells induced by CoronaVac but not BNT162b2 in adolescents. The implications of the differential ability to induce S- and non-S-specific antibody and T cell responses on the durability of protection and protection against virus variants by BNT162b2 and CoronaVac, the 2 most used SARS-CoV-2 vaccines in the world, should be further investigated. Our results support the use of both vaccines in adolescents.
... Moreover, we must consider that correlates of protection can vary in different populations (e.g., SARS-CoV-2 infected, COVID-19 vaccinees, or immunocompromised individuals) [9,[16][17][18], for different vaccine formulation [19], upon the emergence of SARS-CoV-2 variants [20,21] and with time from vaccination or infection. ...
To investigate the dynamic association among binding and functional antibodies in health-care-workers receiving two doses of BNT162b2 mRNA COVID-19-vaccine, SARS-CoV-2 anti-RBD IgG, anti-Trimeric-S IgG, and neutralizing antibodies (Nabs) were measured in serum samples collected at 2 weeks, 3 months, and 6 months from full vaccination. Despite the high correlation, results for anti-RBD and anti-Trimeric S IgG were numerically different even after recalculation to BAU/mL following WHO standards indications. Moreover, after a peak response at 2 weeks, anti-RBD IgG levels showed a 4.5 and 13 fold decrease at 3 and 6 months, respectively, while the anti-Trimeric S IgG presented a less pronounced decay of 2.8 and 4.7 fold. Further different dynamics were observed for Nabs titers, resulting comparable at 3 and 6 months from vaccination. We also demonstrated that at NAbs titers ≥40, the area under the receiver operating characteristic curve and the optimal cutoff point decreased with time from vaccination for both anti-RBD and anti-Trimeric S IgG. The mutating relation among the anti-RBD IgG, anti-Trimeric S IgG, and neutralizing antibodies are indicative of antibody maturation upon vaccination. The lack of standardized laboratory procedures is one factor interfering with the definition of a correlate of protection from COVID-19.
... The term "correlate of protection" refers to a laboratory parameter associated with protection from a clinical disease [1]. The immunological correlates of protection against SARS-CoV-2 infection have not been identified yet. ...
SARS-CoV-2-specific CD8+ T cell immunity is expected to counteract viral variants in both efficient and durable ways. We recently described a way to induce a potent SARS-CoV-2 CD8+ T immune response through the generation of engineered extracellular vesicles (EVs) emerging from muscle cells. This method relies on intramuscular injection of DNA vectors expressing different SARS-CoV-2 antigens fused at their N-terminus with the Nefmut protein, i.e., a very efficient EV-anchoring protein. However, quality, tissue distribution, and efficacy of these SARS-CoV-2-specific CD8+ T cells remained uninvestigated. To fill the gaps, antigen-specific CD8+ T lymphocytes induced by the immunization through the Nefmut-based method were characterized in terms of their polyfunctionality and localization at lung airways, i.e., the primary targets of SARS-CoV-2 infection. We found that injection of vectors expressing Nefmut/S1 and Nefmut/N generated polyfunctional CD8+ T lymphocytes in both spleens and bronchoalveolar lavage fluids (BALFs). When immunized mice were infected with 4.4 lethal doses of 50% of SARS-CoV-2, all S1-immunized mice succumbed, whereas those developing the highest percentages of N-specific CD8+ T lymphocytes resisted the lethal challenge. We also provide evidence that the N-specific immunization coupled with the development of antigen-specific CD8+ T-resident memory cells in lungs, supporting the idea that the Nefmut-based immunization can confer a long-lasting, lung-specific immune memory. In view of the limitations of current anti-SARS-CoV-2 vaccines in terms of antibody waning and efficiency against variants, our CD8+ T cell-based platform could be considered for a new combination prophylactic strategy.
... Correlates of protection [4] for SARS-CoV-2 are not yet firmly established [5], but a growing body of evidence suggests that neutralizing antibody levels are highly predictive for protection against symptomatic disease [6][7][8][9][10][11][12][13]. While very limited empirical evidence exists specifically about the Sinopharm vaccine in this respect, traditional immunology knowledge and experience with prior vaccines suggest that the technology of the Sinopharm vaccine (whole inactivated virion with alum adjuvant) results in a Th2-skewed immune response [14,15]. ...
Background
Limited information is available on the effectiveness of the BBIBP-CorV (Sinopharm, Beijing CNBG) vaccine, especially in the elderly, despite the fact that it is approved in more than 50 countries.
Methods
RBD-specific antibody titres, as a rapidly available and highly predictive surrogate marker, were measured after two doses of the BBIBP-CorV vaccine in 450 subjects. Results were analyzed in a multivariable model accounting for age, sex and time since the administration of the second dose of the vaccine.
Results
Sex and time since the second dose had little association with the antibody titres. Age, however, was highly relevant: measurable antibody levels were present in about 90% of individuals below the age of 50, but antibody production after BBIBP-CorV vaccination was strongly reduced with increasing age. A large number of elderly subjects, reaching 25% at 60 years, and up to 50% at ages over 80, were found not to produce any protective antibody.
Conclusions
RBD-specific antibody titre, as a correlate of protection for COVID-19 disease susceptibility, should help to evaluate the effectiveness of the BBIBP-CorV vaccine. Results suggest that proper measures should be undertaken to prevent a potential outbreak of COVID-19 in BBIBP-CorV vaccinated but eventually unprotected elderly individuals.
Pseudotyped viruses are more and more widely used in virus research and the evaluation of antiviral products because of their high safety, simple operation, high accessibility, ease in achieving standardization, and high throughput. The development of measures based on pseudotyped virus is closely related to the characteristics of viruses, and it is also necessary to follow the principles of assay development. Only in the process of method development, where the key parameters that affect the results are systematically optimized and the preliminary established method is fully validated, can the accuracy, reliability, and repeatability of the test results be ensured. Only the method established on this basis can be transferred to different laboratories and make the results of different laboratories comparable. This paper summarizes the specific aspects and general principles in the development of assays based on pseudotyped virus, which is of reference value for the development of similar methods.
Vaccination is considered one of the most successful strategies to prevent infectious diseases. In the event of a pandemic or epidemic, the rapid development and distribution of the vaccine to the population is essential to reduce mortality, morbidity and transmission. As seen during the COVID-19 pandemic, the production and distribution of vaccines has been challenging, in particular for resource-constrained settings, essentially slowing down the process of achieving global coverage. Pricing, storage, transportation and delivery requirements of several vaccines developed in high-income countries resulted in limited access for low-and-middle income countries (LMICs). The capacity to manufacture vaccines locally would greatly improve global vaccine access. In particular, for the development of classical subunit vaccines, the access to vaccine adjuvants is a pre-requisite for more equitable access to vaccines. Vaccine adjuvants are agents required to augment or potentiate, and possibly target the specific immune response to such type of vaccine antigens. Openly accessible or locally produced vaccine adjuvants may allow for faster immunization of the global population. For local research and development of adjuvanted vaccines to expand, knowledge on vaccine formulation is of paramount importance. In this review, we aim to discuss the optimal characteristics of a vaccine developed in an emergency setting by focusing on the importance of vaccine formulation, appropriate use of adjuvants and how this may help overcome barriers for vaccine development and production in LMICs, achieve improved vaccine regimens, delivery and storage requirements.
The frequent emergence of SARS-CoV-2 variants thwarts the prophylactic and therapeutic countermeasures confronting COVID-19. Among them, the Delta variant attracts widespread attention due to its high pathogenicity and fatality rate compared with other variants. However, with the emergence of new variants, studies on Delta variants have been gradually weakened and ignored. In this study, a replication-competent recombinant virus carrying the S protein of the SARS-CoV-2 Delta variant was established based on the vesicular stomatitis virus (VSV), which presented a safe alternative model for studying the Delta variant. The recombinant virus showed a replication advantage in Vero E6 cells, and the viral titers reach 107.3 TCID50/mL at 36 h post-inoculation. In the VSV-vectored recombinant platform, the spike proteins of the Delta variant mediated higher fusion activity and syncytium formation than the wild-type strain. Notably, the recombinant virus was avirulent in BALB/c mice, Syrian hamsters, 3-day ICR suckling mice, and IFNAR/GR−/− mice. It induced protective neutralizing antibodies in rodents, and protected the Syrian hamsters against the SARS-CoV-2 Delta variant infection. Meanwhile, the eGFP reporter of recombinant virus enabled the visual assay of neutralizing antibodies. Therefore, the recombinant virus could be a safe and convenient surrogate tool for authentic SARS-CoV-2. This efficient and reliable model has significant potential for research on viral-host interactions, epidemiological investigation of serum-neutralizing antibodies, and vaccine development.
Les muqueuses sont les principales voies d’entrée pour les agents infectieux. Par conséquent, le système immunitaire muqueux a évolué afin d’être la première ligne de défense prévenant les invasions de pathogènes. Ce système immunitaire, bien que commun aux différents tissus, est cependant très compartimentalisé. Ainsi, lors de l’administration muqueuse d’antigènes, un effet vaccinal peut être induit localement mais aussi dans la circulation systémique et au niveau de sites muqueux distants. Par la voie sublinguale, il est notamment possible d’observer une réponse humorale et cellulaire au niveau de la salive et des muqueuses vaginales et rectales. La vaccination par voie buccale présente donc un avantage certain dans le développement de formulations pour combattre des agents infectieux et notamment des pathogènes nécessitant une forte réponse immunitaire muqueuse tel que le VIH. De nombreux obstacles freinent en effet le développement de vaccins contre ce virus, parmi lesquelles l’induction d’une réponse humorale et cellulaire muqueuse difficilement atteignable par la vaccination par injection. Parmi les alternatives envisageables, la vaccination sublinguale présente donc de nombreux avantages parmi lesquelles une délivrance sûre, accessible et rapide de composés prophylactiques. De plus, cette voie d’administration est également moins contraignante que les vaccins « traditionnels ». Cependant, la vaccination sublinguale n’est encore que partiellement développée puisque les formulations sont généralement délivrées sous forme liquide, ce qui induit des réponses immunitaires particulièrement hétérogènes, principalement dû à un fort taux de dispersion du vaccin dans la salive. L’objectif de mon projet est donc de mettre au point un patch de vaccination sublingual permettant d’accueillir différentes formulations en vue de permettre l’induction d’une réponse muqueuse anti-VIH-1. Composé de polymères biocompatibles et biodégradables, ce support vise à prolonger la délivrance d’agents actifs au niveau du site sublingual afin d’intensifier la réponse immunitaire induite. Nous avons donc mis au point une structure solide capable d’accueillir certaines protéines et agents nanoparticulaires pouvant composer un vaccin, tout en démontrant in vitro la préservation de leur bioactivité au sein de cette dernière. Nous avons par la suite pu confirmer la biocompatibilité de cet assemblage polymérique in vitro par évaluation cytotoxique et in vivo, par analyse histologique et quantification de la sécrétion locale de cytokines pro-inflammatoires après administration buccale du patch. Dans un modèle murin, l’analyse de la libération d’un antigène incorporé au sein de cette structure nous a également permis de démontrer une prolongation du temps de contact entre la muqueuse sublinguale et la formulation par rapport à une libération liquide, démontrant ainsi les propriétés mucoadhésives du dispositif. La quantification d’un panel de cytokines pro-inflammatoires sécrétées localement et dans le compartiment systémique nous a permis de mettre en évidence le maintien des signatures cytokiniques après délivrance de différentes formulations. Ces résultats démontrent à la fois la versatilité du patch ainsi que sa capacité à accueillir de nombreuses formulations vaccinales tant protéiques que nanoparticulaires. Finalement, nous avons effectué une étude in vivo sur la réponse humorale par quantification d’anticorps spécifiques des antigènes incorporés dans nos patchs. Cette dernière a révélé la capacité de l’immunisation sublinguale à induire la sécrétion de SIgA dans les fèces et le sérum, soulignant ainsi la bioactivité de certaines de nos formulations. D’après ces observations, l’intégration d’un vaste panel d’antigènes et d’adjuvants au sein de notre système de délivrance permet la libération de ces derniers au niveau du compartiment sublingual, stimulant ainsi l’induction d’une réponse immunitaire intensifiée en comparaison à une administration liquide.
Background
The identification of baseline host determinants that associate with robust HIV-1 vaccine-induced immune responses could aid HIV-1 vaccine development. We aimed to assess both the collective and relative performance of baseline characteristics in classifying individual participants in nine different Phase 1-2 HIV-1 vaccine clinical trials (26 vaccine regimens, conducted in Africa and in the Americas) as High HIV-1 vaccine responders.
Methods
This was a meta-analysis of individual participant data, with studies chosen based on participant-level (vs. study-level summary) data availability within the HIV-1 Vaccine Trials Network. We assessed the performance of 25 baseline characteristics (demographics, safety haematological measurements, vital signs, assay background measurements) and estimated the relative importance of each characteristic in classifying 831 participants as High (defined as within the top 25th percentile among positive responders or above the assay upper limit of quantification) versus Non-High responders. Immune response outcomes included HIV-1-specific serum IgG binding antibodies and Env-specific CD4+ T-cell responses assessed two weeks post-last dose, all measured at central HVTN laboratories. Three variable importance approaches based on SuperLearner ensemble machine learning were considered.
Findings
Overall, 30.1%, 50.5%, 36.2%, and 13.9% of participants were categorized as High responders for gp120 IgG, gp140 IgG, gp41 IgG, and Env-specific CD4+ T-cell vaccine-induced responses, respectively. When including all baseline characteristics, moderate performance was achieved for the classification of High responder status for the binding antibody responses, with cross-validated areas under the ROC curve (CV-AUC) of 0.72 (95% CI: 0.68, 0.76) for gp120 IgG, 0.73 (0.69, 0.76) for gp140 IgG, and 0.67 (95% CI: 0.63, 0.72) for gp41 IgG. In contrast, the collection of all baseline characteristics yielded little improvement over chance for predicting High Env-specific CD4+ T-cell responses [CV-AUC: 0.53 (0.48, 0.58)]. While estimated variable importance patterns differed across the three approaches, female sex assigned at birth, lower height, and higher total white blood cell count emerged as significant predictors of High responder status across multiple immune response outcomes using Approach 1. Of these three baseline variables, total white blood cell count ranked highly across all three approaches for predicting vaccine-induced gp41 and gp140 High responder status.
Interpretation
The identified features should be studied further in pursuit of intervention strategies to improve vaccine responses and may be adjusted for in analyses of immune response data to enhance statistical power.
Funding
National Institute of Allergy and Infectious Diseases (UM1AI068635 to YH, UM1AI068614 to GDT, UM1AI068618 to MJM, and UM1 AI069511 to MCK), the Duke CFAR P30 AI064518 to GDT, and National Institute of Dental and Craniofacial Research (R01DE027245 to JJK). This work was also supported by the Bill and Melinda Gates Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding sources.
Vaccines are all biological substances produced from living things, administered to trigger the host's body defense system to develop immunity against a specific pathogen from which they are produced. They are produced either from the whole organism or parts of it. There are several types of vaccines like live virulent, live attenuated, inactivated (killed), subunit, toxoid, sero-vaccine, and autogenous vaccine. Vaccines work by stimulating either humoral or cell-mediated immunity or both to differentiate. Even though vaccination is the powerful and cost-effective weapon of disease prevention and control of infectious and non infectious diseases, there are factors those, hinder its effectiveness (constraints of vaccine effectiveness). These factors are technical constraints, pathogen-related constraints, vaccine-related factors, host-related and environmental and management-related constraints. While planning a vaccination regimen, it is important to test the potency of the vaccine, whether it much with circulating serotype, availability of cold chain, skilled manpower, the status of the target group and weather condition. Vaccine epidemiology, the study of vaccine interactions and impacts on the epidemiology of vaccine-preventable diseases also has an impact on vaccine effectiveness. it includes basic reproductive number, the force of infection, herd immunity, and epidemiologic shift. Some review papers mostly deal with constraints of specific vaccines and species of animals and with a specific constraint of the vaccine. However, the papers which review all common constraints of vaccine are limited. Therefore, this review paper is to address the most common constraints on the effectiveness of vaccines in all animal species and to highlight on evaluation of vaccine effectiveness and epidemiology.
Résumé
Le nombre d’enfants adoptés en France ou à l’international diminue depuis 2004, avec des enfants caractérisés par un âge plus élevé, des fratries, un vécu de ruptures plus nombreuses et des pathologies physiques, développementales, comportementales et/ou psychologiques nécessitant des soins plus ou moins durables, qui préoccupent les parents adoptants. Les médecins peuvent être sollicités en préadoption sur un dossier d’enfant ou pour des conseils de pédiatrie générale. Ils peuvent aussi évaluer cliniquement et par des examens complémentaires un enfant récemment arrivé. Ils sont également interrogés par des parents dont l’enfant adopté présente des troubles somatiques et/ou psychosociaux pendant ou après la période de transition, et en particulier lors des questionnements identitaires de l’adolescence. Cet article a pour but de donner des moyens de compréhension et de prise en charge des situations de consultations d’enfant adopté que le praticien peut rencontrer. Les pathologies le plus fréquemment observées à l’arrivée sont des infections intestinales et cutanées, des malnutritions et des troubles psychocomportementaux. Certaines infections et intoxications potentiellement graves et rares sont dépistées systématiquement (tuberculose, hépatites virales, syphilis, virus de l’immunodéficience humaine, etc.) ou selon les facteurs d’exposition au risque (paludisme, alcoolisation fœtale, saturnisme, etc.). Une évaluation de l’immunité vaccinale et un rattrapage éventuel sont nécessaires précocement. Au cours du suivi, les motifs fréquents de consultation sont la dynamique de croissance, l’incertitude de l’âge, des troubles développementaux (motricité, langage, sommeil et/ou alimentation), des troubles psychoaffectifs et de l’attachement et la puberté avancée. La connaissance des problématiques actuelles de l’adoption est nécessaire et permet d’éviter d’attribuer n’importe quel symptôme à l’adoption. Il existe des consultations d’adoption multidisciplinaires (pédiatres, pédopsychiatres, psychologue en lien avec un réseau de spécialistes) dans la plupart des régions de France et des pays d’adoption qui sont des centres de référence pour répondre aux situations complexes.
Introduction
Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen in the world. A licensed vaccine is not yet available, but the first vaccines have entered clinical trials.
Areas covered
: We describe the progress that has been made in our understanding of the type of immunity that a protective vaccine should induce, and the challenges that vaccine developers face. We also focus on the clinical development of a chlamydia vaccine. The first chlamydia vaccine candidate has now been tested in a clinical phase-I trial, and another phase-I trial is currently running. We discuss what it will take to continue this development and what future trial setups could look like.
Expert opinion
The chlamydia field is coming of age and the first phase I clinical trial of a C. trachomatis vaccine has been successfully completed. We expect and hope that this will motivate various stakeholders to support further development of chlamydia vaccines in humans.
The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is a conserved domain and a target for neutralizing antibodies. We defined the carbohydrate content of the recombinant RBD produced in different mammalian cells. We found a higher degree of complex-type N-linked glycans, with less sialylation and more fucosylation, when the RBD was produced in human embryonic kidney cells compared to the same protein produced in Chinese hamster ovary cells. The carbohydrates on the RBD proteins were enzymatically modulated, and the effect on antibody reactivity was evaluated with serum samples from SARS-CoV-2 positive patients. Removal of all carbohydrates diminished antibody reactivity, while removal of only sialic acids or terminal fucoses improved the reactivity. The RBD produced in Lec3.2.8.1-cells, which generate carbohydrate structures devoid of sialic acids and with reduced fucose content, exhibited enhanced antibody reactivity, verifying the importance of these specific monosaccharides. The results can be of importance for the design of future vaccine candidates, indicating that it is possible to enhance the immunogenicity of recombinant viral proteins.
Objective
A prophylactic vaccine is needed to control the HCV epidemic, with genotypes 1–3 causing >80% of worldwide infections. Vaccine development is hampered by HCV heterogeneity, viral escape including protection of conserved neutralising epitopes and suboptimal efficacy of HCV cell culture systems. We developed cell culture-based inactivated genotype 1–3 HCV vaccine candidates to present natively folded envelope proteins to elicit neutralising antibodies.
Design
High-yield genotype 1a, 2a and 3a HCV were developed by serial passage of TNcc, J6cc and DBN3acc in Huh7.5 cells and engineering of acquired mutations detected by next-generation sequencing. Neutralising epitope exposure was determined in cell-based neutralisation assays using human monoclonal antibodies AR3A and AR4A, and polyclonal antibody C211. BALB/c mice were immunised with processed and inactivated genotype 1a, 2a or 3a viruses using AddaVax, a homologue of the licenced adjuvant MF-59. Purified mouse and patient serum IgG were assayed for neutralisation capacity; mouse IgG and immune-sera were assayed for E1/E2 binding.
Results
Compared with the original viruses, high-yield viruses had up to ~1000 fold increased infectivity titres (peak titres: 6–7 log10 focus-forming units (FFU)/mL) and up to ~2470 fold increased exposure of conserved neutralising epitopes. Vaccine-induced IgG broadly neutralised genotype 1–6 HCV (EC50: 30–193 µg/mL; mean 71 µg/mL), compared favourably with IgG from chronically infected patients, and bound genotype 1–3 E1/E2; immune-sera endpoint titres reached up to 32 000.
Conclusion
High-yield genotype 1–3 HCV could be developed as basis for inactivated vaccine candidates inducing broadly neutralising antibodies in mice supporting further preclinical development.
The emergence of safe and effective mRNA platform-based COVID-19 vaccines from the recent pandemic has changed the face of vaccine development. Compared with conventional technologies used historically, mRNA-based vaccines offer a rapid flexible and robust approach to preventing disease caused by transient viral strains such as SAR2-CoV-2 variants of concern and seasonal influenza. Adaptations in the formulation of the mRNA delivery systems such as with lipid nanoparticle delivery (LNP) used in mRNA-1273 and BNT16b2b have enabled this technology to flourish under the urgent collective response and collaborative regulatory understanding derived from COVID-19 vaccine development. The application of mRNA-based therapeutics in other areas holds potential promise including combination vaccines that might deliver protections against multiple infectious diseases. Future studies and further advances in mRNA-based technologies will provide insight into the clinical efficacy and real-world effectiveness of vaccines as well as provisions with respect to the impact of reactogenicity profiles. Overall, the success of mRNA-based COVID-19 vaccines has helped unlock a platform likely to result in many more candidate vaccines entering clinical evaluation to address the unmet medical needs of other diseases including viral respiratory diseases, herpesviruses, and historically challenging vaccine targets such as HIV.
Abstract Background The initiation of a new drug, for instance, the coronavirus disease 2019 (COVID-19) vaccine in children could be a source of major concern for parents. This study aims to determine the willingness of parents in Malaysia to vaccinate their children younger than 12 years against COVID-19. Methods An online cross-sectional survey was conducted nationwide in Malaysia from August 29, 2021, to October 17, 2021. Parents with children younger than 12 years were enrolled via the snowball sampling method. Results The analysis included data from 3,528 parents (79.5%) of the 4,438 survey responses received. Of these parents, 2,598 (73.6%) were willing, 486 (13.8%) were not willing, and 444 (12.6%) were still hesitant to vaccinate their children against COVID-19. Single parents (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.32–3.04; P = 0.001), parents with secondary or lower education (OR, 1.5; 95% CI, 1.21–1.96; P
Vaccination is an important strategy for preventing infectious diseases caused by bacteria and viruses in fish. Worldwide, there are continuous efforts to develop vaccines against bacterial and viral pathogens or improve the protection and duration of immunity of the existing vaccines. However, still many countries including India have only demonstrated development of vaccines under laboratory conditions, but do not have commercial vaccines for application in aquaculture. Trials of experimental vaccines must include data on efficacy of vaccines in terms of eliciting protective immune response in the host. Calculating relative percent survival (RPS) or measuring specific antibody level as a correlate of protection or indirect ELISA for estimating antibody levels in the host after immunization need to be evaluated to demonstrate the efficacy of trial vaccine under laboratory and field conditions.
In this chapter, we discuss the challenge of vaccinating immunocompromised individuals with live-attenuated vaccine, which are mostly contraindicated given the fear of a theoretical uncontrolled replication that could lead to severe vaccine-induced disease. We present the safety and immunogenicity data available on measles-mumps-rubella (MMR) vaccine, varicella vaccine, or any other live-attenuated vaccine in children with rheumatic diseases, solid organ transplant (SOT), or hematopoietic stem cell transplant. We show that there is increasing evidence to suggest that MMR and varicella vaccines are well tolerated in individuals with mild immunosuppression, liver or kidney transplant recipients (strict conditions), after hematopoietic stem cell transplantation, or in individuals with dysimmune disorders on low/no immunosuppressant therapy. As both vaccines have the potential to protect patients against threatening pathogens that are endemic or linked to epidemics worldwide, we discuss the current guidelines for MMR vaccine and varicella vaccine in the various imuunosuppressive conditions. We also provide a brief overview on the data available on live-attenuated vaccine following treatment with intravenous immunoglobulin or in infants born to mothers who received immunosuppressive treatment during pregnancy.KeywordsLive-attenuated vaccineMeasles-mumps-rubella vaccineVaricella vaccineVaccine responsesSafetyImmunodeficiencyDysimmune disordersRheumatic diseasesSolid organ transplantHematopoietic stem cell transplant
Trained immunity is defined as the de facto memory characteristics induced in innate immune cells after exposure to microbial stimuli after infections or certain types of vaccines. Through epigenetic and metabolic reprogramming of innate immune cells after exposure to these stimuli, trained immunity induces an enhanced nonspecific protection by improving the inflammatory response upon restimulation with the same or different pathogens. Recent studies have increasingly shown that trained immunity can, on the one hand, be induced by exposure to viruses; on the other hand, when induced, it can also provide protection against heterologous viral infections. In this review we explore current knowledge on trained immunity and its relevance for viral infections, as well as its possible future uses.
Expected final online publication date for the Annual Review of Virology, Volume 9 is September 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Objectives
Serum salmonellacidal (bactericidal) antibody could be used to detect functional capacity of antibody in patients with enteric fever and after typhoid vaccination.
Methods
Salmonellacidal antibody response was measured by colorimetric serum salmonellacidal assay in 70 acute and 11 convalescence sera of Salmonella Typhi and Paratyphi A infected patients, and also in 15 control and 06 Vi polysaccharide vaccinated volunteer's sera.
Results
Sera from typhoid and paratyphoid A patients showed significant (p<0.05) levels of salmonellacidal antibody titer (549.9±108.5 and 528.7±187.3) compared to control (0.133±0.1). Moreover, this titer increased significantly (p<0.05) in samples collected between 7 to 10 days and between 11 to 25 days of fever (titer 535.7± 119.2 and 794.6± 235.6) compared to fever for less than 7 days (136.4± 52.7). The mean titer significantly (p<0.05) decreased to 5.5±2.1 after 6-8 weeks onset of illness. Though, very low salmonellacidal titers (2.5±1.5 and 2.3±1.5) were detected after Vi CPS vaccine among the human volunteers, but mean titer raised 15 fold from pre to post vaccinated sera (0.166 to 2.5).
Conclusion
The serum salmonellacidal antibody by colorimetric salmonellacidal assay could be used to detect acute typhoidal cases and also to monitor immune response of typhoid vaccine.
Vaccination to prevent and even eliminate disease is amongst the greatest achievements of modern medicine. Opportunities remain in vaccine development to improve protection across the whole population. A next step in vaccine development is the detailed molecular characterization of individual humoral immune responses against a pathogen, especially the rapidly evolving pathogens. New technologies such as sequencing the immune repertoire in response to disease, immunogenomics/vaccinomics, particularly the individual HLA variants, and high-throughput epitope characterization offer new insights into disease protection. Here, we highlight the emerging technologies that could be used to identify variation within the human population, facilitate vaccine discovery, improve vaccine safety and efficacy, and identify mechanisms of generating immunological memory. In today’s vaccine-hesitant climate, these techniques used individually or especially together have the potential to improve vaccine effectiveness and safety and thus vaccine uptake rates. We highlight the importance of using these techniques in combination to understand the humoral immune response as a whole after vaccination to move beyond neutralizing titers as the standard for immunogenicity and vaccine efficacy, especially in clinical trials.
Background
Parasitic infections are prime causes of morbidity and mortality worldwide. Significant progress has been made to cure these infections like discovery of antiparasitic drugs, developing new formulation strategies and site-directed drug delivery and chemotherapy etc. As synthetic drugs are perilous and have various side effects leading to the development of drug resistance and loss of health. Herbal medicines are economical and generally free from potential side effects is acclaiming recognition. However, it is difficult to produce antiparasitic vaccines, major efforts have been made and still there are no licensed vaccines currently available to control human parasitic ailments.
Area covered
Here, a systematic review is dispensed assessing various techniques for the treatment of parasitic infections. Moreover, the advancements and challenges involved in establishing novel trends in the development of a more effective drug delivery systems are also investigated.
Conclusion
The numbers of impending infectious ailments in humans have enhanced within the novel past or warn to increase in the future. Over thirty new infective agents have been identified globally in the last 30 years; approximately 60 % of these are from zoonotic sources. Efficient drug delivery plays a key role in treating parasitic infections. The main goal of modern antiparasitic drug delivery system is to minimize the potential side effects and bring the drug directly to the target pathogens, therefore, more sophisticated drug formulations than a simple tablet or solution are necessary for the betterment of critical situations of many human parasitic diseases.
The development of an effective HIV-1 vaccine remains a scientific and global health priority despite nearly four decades of intensive investigation. A major roadblock to rational HIV-1 vaccine design is the lack of a primate model in which broadly neutralizing antibodies (bNAbs) can be commonly induced, thereby enabling the molecular and immunological mechanisms responsible for such responses to be studied reproducibly and iteratively. We hypothesized that one means to elicit such antibodies in primates might be by infecting rhesus macaques (RMs) with simian-human immunodeficiency viruses (SHIVs) that bear primary HIV-1 envelope glycoproteins (Envs). Here, we chose to investigate rhesus bNAbs targeting the V2 apex epitope of Env, as human V2 apex bNAbs share several defining characteristics that make them attractive vaccine candidates. We constructed 17 novel SHIVs bearing genetically diverse HIV-1 Envs and used these viruses to infect 127 RMs. Approximately 20% of RMs developed bNAbs that exhibited a wide range of breadth and potency after four months to three years of SHIV infection, half of which recognized the V2 apex. We isolated nine rhesus monoclonal V2 apex bNAb lineages, the characterization of which revealed conserved immunogenetic, chemical, and phenotypic solutions to epitope recognition that recapitulated key features of human V2 apex bNAbs. This included atypically long and anionic heavy chain complementarity-determining region 3s (HCDR3s) derived from an identical IGHD gene that are tyrosine-sulfated and make critical contacts with cationic residues in the C-strand, a key component of the V2 apex epitope. CryoEM structures of two rhesus bNAbs revealed structural mimicry of two distinct HCDR3 topologies that define the PGT145 and VRC26-classes of human V2 apex bNAbs. In eight donor macaques, SHIV Env evolution within or proximal to the C-strand was temporally associated with the development of V2 apex-mediated neutralization breadth and exhibited patterns like that of Env evolution in HIV-1 infected humans with V2 apex bNAbs. The molecular Env-Ab coevolutionary pathway of one rhesus lineage reveals striking similarities of V2 apex bNAb ontogeny in RMs and humans. Overall, SHIV-induced rhesus V2 apex bNAbs can recapitulate developmental features of human bNAbs, thereby guiding HIV-1 V2 apex vaccine design.
The Omicron variant of SARS-CoV-2 has been shown to evade neutralizing antibodies elicited by vaccination or prior infection. Despite the dramatic global spread of the Omicron variant, even among highly vaccinated populations, death rates have not increased concomitantly. These data suggest that immune mechanisms beyond antibody-mediated virus neutralization may protect against severe disease. In addition to neutralizing pathogens, antibodies contribute to control and clearance of infections through Fc-effector mechanisms. Here we probed the ability of vaccine-induced antibodies to drive Fc-effector activity against the Omicron variant using samples from individuals receiving one of three SARS-CoV-2 vaccines. Despite a substantial loss of IgM, IgA, and IgG binding to the Omicron variant Receptor Binding Domain (RBD) in samples from individuals receiving BNT162b2, mRNA-1273, and CoronaVac vaccines, stable binding was maintained against the full-length Omicron Spike protein. Compromised RBD binding IgG was accompanied by a loss of cross RBD-specific antibody Fcγ receptor (FcγR) binding in samples from individuals who received the CoronaVac vaccine, but RBD-specific FcγR2a and FcγR3a binding was preserved in recipients of mRNA vaccines. Conversely, Spike protein-specific antibodies exhibited persistent but reduced binding to FcγRs across all three vaccines, though higher binding was observed in samples from recipients of mRNA vaccines. This was associated with preservation of FcγR2a and FcγR3a binding antibodies and maintenance of Spike protein-specific antibody-dependent natural killer cell activating antibodies. Thus, despite the loss of Omicron neutralization, vaccine-induced Spike protein-specific antibodies continue to drive Fc-effector functions, suggesting a capacity for extra-neutralizing antibodies to contribute to disease control.
Preexisting immunity to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) was nonexistent in humans, which coupled with high transmission rates of certain SARS-CoV-2 variants and limited vaccine uptake or availability, has collectively resulted in an ongoing global pandemic. The identification and establishment of one or multiple correlates of protection (CoP) against infectious pathogens is challenging, but beneficial from both the patient care and public health perspectives. Multiple studies have shown that neutralizing antibodies, whether generated following SARS-CoV-2 infection, vaccination, or a combination of both (i.e., hybrid immunity), as well as adaptive cellular immune responses, serve as CoPs for COVID-19. However, the diverse number and type of serologic assays, alongside the lack of cross-assay standardization and emergence of new SARS-CoV-2 variants with immune evasive characteristics, have collectively posed challenges to determining a robust CoP 'threshold' and for the routine utilization of these assays to document 'immunity,' as is commonly done for other vaccine preventable diseases. Here, we discuss what CoPs are, review our current understanding of infection-induced, vaccine-elicited and hybrid immunity to COVID-19 and summarize the current and potential future utility of SARS-CoV-2 serologic testing.
Abstract Vaccination represents one of the most important achievements in modern medicine. During the era of COVID‐19 pandemic, the successful vaccination for SARS‐COV‐2 is the major hope to bring the society back to normal. However, although vaccines, such as for smallpox and poliomyelitis, can trigger life‐long protection in individuals and help to generate the herd immunity resulting in the eradication of pathogens, other vaccines, with seasonal influenza vaccine as a case in point, are unable to induce sustained immunity so that repeated vaccination is required. As most vaccines were developed empirically, the immunological mechanism underlying the longevity of vaccine‐induced protection remains only partially understood. In this review, we first describe vaccine‐induced humoral immune response in which long‐lived plasma cells and memory B cells are produced. We then summarise methods using immunological correlates of protection to assess the longevity of vaccine efficacy and provide the evidence and knowledge for the duration of protection by current vaccines. Last, we discuss rationale and strategies to improve the duration of vaccine protection by targeting vaccine immunogenicity, antibody affinity, avidity and prime‐boost scheme.
The data from our 1968-69 influenza vaccine field trials are anlaysed and pre-challenge haemagglutinin and neuraminidase serum antibodies are evaluated as indices of protection. Prevention of flu-like disease, fever, confinement to bed, and/or seroconversion to Hong Kong was significantly related to post-vaccine A/Hong Kong/68(H3N2) haemagglutination-inhibition (HI) titres. Prevention of disease was also related, although not significantly statistically in every category, to pre-challenge A/Hong Kong/68 neuraminidase inhibition (NI) titres. The trend was the same regardless of whether the origin of the NI antibody was through A/Aichi/68 or A/Japan/62 vaccines or through pre-Hong Kong influenza infections. In summarizing the data using fever as an index of disease, the attack rate (AR) among volunteers without Hong Kong NI or HI antibody was 45%. Presence of NI antibody, in the absence of HI antibody, significantly reduced the AR to 24%. Those with both NI and HI titres experienced a still lower AR of 14%. Those with HI and NI titres both > 1: 160 ran little risk of disease, with an AR of 7%.
A school blood drive before a measles outbreak permitted correlation of preexposure measles antibody titers with clinical
protection using the plaque reduction neutralization (PRN) test and an EIA. Of 9 donors with detectable preexposure PRN titer
⩽120, 8 met the clinical criteria for measles (7 seroconfirmed) compared with none of 71 with preexposure PRN titers >120
(P < .0001). Seven of 11 donors with preexposure PRN titers of 216–874 had a ⩾4-fold rise in antibody titer (mean, 43-fold)
compared with none of 7 with a preexposure PRN titer ⩾1052 (P < .02). Of 37 noncases with preexposure PRN titer <1052, 26
(70%) reported one or more symptoms compared with 11 (31%) of 35 donors with preexposure PRN titers ⩾1052 (P < .002). By EIA,
no case had detectable preexposure antibody; the preexposure geOlpetric mean titer of asymptomatic donors (220) was not significantly
higher than that of symptomatic donors who did not meet the clinical criteria for measles (153) (P = .10). The study suggests that PRN titers ~120 were not protective against measles disease and illness without rash due
to measles may occur in persons with PRN titers above this level.
This study assessed the level of vaccine-induced hepatitis B surface antibody that is protective against hepatitis B infection
and carriage in The Gambia. Sera from 700 of a cohort of 1041 children vaccinated against hepatitis B in infancy were serially
tested for markers of hepatitis B until age 7 years. No absolute level of protection against infection was found, but all
children who attained a peak antibody response to vaccination of ⩾10 IU/L were protected against carriage of hepatitis B surface
antigen. Two-thirds of 45 infected children experienced brief infection (determined by loss of core antibody). This transient
infection was likely related to surface antibody level. The data support the use of the peak antibody response as the best
indicator of protection against carriage and suggest that most infections after vaccination are short-lived.
The significance of reduced antibody responses to the Haemophilus influenzae type b (Hib) component of acellular pertussis—containing combination vaccines (DTaP-Hib) is unclear. A DTaP-Hib vaccine evaluated
in infants vaccinated at ages 2, 3, and 4 months showed reduced anti-Hib polysaccharide IgG (geometric mean concentration
[GMC], 1.23 µg/mL; 57%, >1.0 µg/mL). Polyribitolribosyl phosphate (PRP) and Hib conjugate (PRP-T) vaccine given as a booster during the second year of life
was evaluated for the presence of immunological memory. After boosting, most children achieved anti-PRP IgG >1.0 µg/mL, although the GMC was higher with PRP-T (88.5 µg/mL) than with PRP vaccine (7.86 µg/mL, P < .001). The GMC of the PRP group was higher than anticipated for naive PRP recipients of the same age. PRP-specific IgG
avidity was significantly higher after boosting than after priming, providing further evidence for the generation of memory.
Despite reduced immunogenicity, DTaP-Hib combination vaccines appear to prime for immunologic memory.
The pneumococcal polysaccharide vaccine is recommended as a means of preventing invasive disease in the elderly. We compared
responses to the 23-valent polysaccharide vaccine in 46 previously unvaccinated, healthy, institutionalized elderly persons
(mean age, 85.5 years) with those in 12 healthy younger adults (mean age, 37 years) by measuring prevaccination and postvaccination
serum IgG antibody concentrations (by ELISA), functional antibody activity (by opsonophagocytosis), IgG antibody avidity,
and passive protection in mice. Postvaccination IgG antibody concentrations for two serotypes (6B and 19F) of the five studied
(4, 6B, 14, 19F, and 23F) were significantly lower in elderly than in younger adults; however, opsonophagocytic activity was
significantly reduced for all serotypes in the elderly. Sera with reduced opsonophagocytic activity (titer, <64) correlated
with low IgG antibody avidity and protected mice poorly against pneumococcal challenge. In elderly persons receiving polysaccharide
vaccination, there was a significant reduction in the functionality of postvaccination antibodies, and this appeared to increase
with advanced age.
The authors conducted a 2-year, multicenter, double-blind, placebo-controlled efficacy field trial of live, attenuated, cold-adapted,
trivalent influenza vaccine administered by nasal spray to children 15–71 months old. Overall, vaccine was 92% efficacious
at preventing culture-confirmed infection by influenza A/H3N2 and influenza B. Because influenza A/H1N1 did not cause disease
during the years in which this study was conducted, the authors sought to determine vaccine efficacy and correlates of immune
protection against experimental challenge with 107 TCID50 of attenuated H1N1 (vaccine strain) by intranasal spray. Prechallenge assessments included serum hemaglutination-inhibiting
(HAI) antibody and nasal wash IgA antibody to H1N1. Vaccine was 83% efficacious (95% confidence interval, 60%–93%) at preventing
shedding of H1N1 virus after challenge. Any serum HAI antibody or any nasal wash IgA antibody was correlated with significant
protection from H1N1 infection as indicated by vaccine-virus shedding, and high efficacy against H1N1 challenge was demonstrated.
All acellular pertussis vaccines contain pertussis toxoid and induce protection against pertussis. This study investigated
the relation between the postvaccination levels of pertussis toxin (PT) serum IgG and protection against pertussis. PT IgG
was determined in sera obtained 21–77 days after the third vaccination from 813 children who received 3 doses of pertussis
toxoid. The children were followed for 21–33 months after vaccination for the occurrence of pertussis. Of the children, 126
were exposed to pertussis in their households. The median PT IgG concentration was 79 U/mL in those who developed severe pertussis
(⩾21 day of paroxysmal cough), 156 U/mL with mild pertussis (<21 days of paroxysmal cough), and 246 U/mL in those who did
not develop pertussis (79 vs. 246, P < .0001). Corresponding values in the 687 children with no household exposure were 99, 124, and 155 U/mL, respectively (99
vs. 155, P < .0001). Thus, there is a highly significant correlation between the level of vaccineinduced serum PT IgG and protection
against pertussis.
Measles remains a principal cause of worldwide mortality, in part because young infants cannot be immunized effectively. Development of new vaccines has been hindered by previous experience with a formalin-inactivated vaccine that predisposed to a severe form of disease (atypical measles). Here we have developed and tested potential DNA vaccines for immunogenicity, efficacy and safety in a rhesus macaque model of measles. DNA protected from challenge with wild-type measles virus. Protection correlated with levels of neutralizing antibody and not with cytotoxic T lymphocyte activity. There was no evidence in any group, including those receiving hemagglutinin-encoding DNA alone, of 'priming' for atypical measles.
Vaccination by anthrax protective antigen (PA)-based vaccines requires multiple immunization, underlying the need to develop more efficacious vaccines or alternative vaccination regimens. In spite of the vast use of PA-based vaccines, the definition of a marker for protective immunity is still lacking. Here we describe studies designed to help define such markers. To this end we have immunized guinea pigs by different methods and monitored the immune response and the corresponding extent of protection against a lethal challenge with anthrax spores. Active immunization was performed by a single injection using one of two methods: (i) vaccination with decreasing amounts of PA and (ii) vaccination with constant amounts of PA that had been thermally inactivated for increasing periods. In both studies a direct correlation between survival and neutralizing-antibody titer was found (r(2) = 0.92 and 0.95, respectively). Most significantly, in the two protocols a similar neutralizing-antibody titer range provided 50% protection. Furthermore, in a complementary study involving passive transfer of PA hyperimmune sera to naive animals, a similar correlation between neutralizing-antibody titers and protection was found. In all three immunization studies, neutralization titers of at least 300 were sufficient to confer protection against a dose of 40 50% lethal doses (LD(50)) of virulent anthrax spores of the Vollum strain. Such consistency in the correlation of protective immunity with anti-PA antibody titers was not observed for antibody titers determined by an enzyme-linked immunosorbent assay. Taken together, these results clearly demonstrate that neutralizing antibodies to PA constitute a major component of the protective immunity against anthrax and suggest that this parameter could be used as a surrogate marker for protection.
In early 2000, a protein-polysaccharide conjugate vaccine targeting seven pneumococcal serotypes was licensed in the United States for use in young children.
We examined population-based data from the Active Bacterial Core Surveillance of the Centers for Disease Control and Prevention to evaluate changes in the burden of invasive disease, defined by isolation of Streptococcus pneumoniae from a normally sterile site. Serotyping and susceptibility testing of isolates were performed. We assessed trends using data from seven geographic areas with continuous participation from 1998 through 2001 (population, 16 million).
The rate of invasive disease dropped from an average of 24.3 cases per 100,000 persons in 1998 and 1999 to 17.3 per 100,000 in 2001. The largest decline was in children under two years of age. In this group, the rate of disease was 69 percent lower in 2001 than the base-line rate (59.0 cases per 100,000 vs. 188.0 per 100,000, P<0.001); the rate of disease caused by vaccine and vaccine-related serotypes declined by 78 percent (P<0.001) and 50 percent (P<0.001), respectively. Disease rates also fell for adults; as compared with base line, the rate of disease in 2001 was 32 percent lower for adults 20 to 39 years of age (7.6 cases per 100,000 vs. 11.2 per 100,000, P<0.001), 8 percent lower for those 40 to 64 years of age (19.7 per 100,000 vs. 21.5 per 100,000, P=0.03), and 18 percent lower for those 65 years of age or more (49.5 per 100,000 vs. 60.1 per 100,000, P<0.001). The rate of disease caused by strains that were not susceptible to penicillin was 35 percent lower in 2001 than in 1999 (4.1 cases per 100,000 vs. 6.3 per 100,000, P<0.001).
The use of the pneumococcal conjugate vaccine is preventing disease in young children, for whom the vaccine is indicated, and may be reducing the rate of disease in adults. The vaccine provides an effective new tool for reducing disease caused by drug-resistant strains.
In October 1992, Haemophilus influenzae type b (Hib) conjugate vaccine was introduced to infants in the United Kingdom with a “catch-up” program for those aged <4
years. Initially, the rate of invasive Hib disease decreased dramatically but has been increasing since 1999. To determine
possible reasons for this increase, the effectiveness of Hib conjugate vaccine was estimated by use of the screening method.
Between October 1993 and December 2001, a total of 443 cases of Hib infection occurred in children eligible for vaccination;
363 (82%) were fully vaccinated. Vaccine effectiveness was estimated to be 56.7% (95% confidence interval, 42.5–67.4). Effectiveness
was lower in children vaccinated during infancy, compared with those who were vaccinated during the catch-up campaign (P=.0033),
declined with time since vaccination (P=.0008), and was lower in children born during 2000–2002, compared with other children
scheduled for infant vaccination (P=.0041). Use of a catch-up vaccination program enhanced the control of Hib infection in
England and Wales. Since 1999, however, low effectiveness in infants, declining effectiveness with age, and the use of lower-efficacy
vaccines have contributed to increased rates of Hib infection. The potential role of boosters needs to be considered
Despite the widespread use of vaccinia virus (VV) as a vector for other Ags and as the smallpox vaccine, there is little information available about the protective components of the immune response following VV infection. In this study, protection against wild-type VV was evaluated in mice with respect to the relative contributions of CD8(+) T cells vs that of CD4(+) T cells and Ab. C57BL/6 mice primed with the Western Reserve strain of VV mount significant IgM and IgG Ab responses, specific cytotoxic T cell responses, IFN-gamma responses in CD4(+) and CD8(+) T cells, and effectively clear the virus. This protection was abrogated by in vivo depletion of CD4(+) T cells or B cells in IgH(-/-) mice, but was not sensitive to CD8(+) T cell depletion alone. However, a role for CD8(+) T cells in primary protection was demonstrated in MHC class II(-/-) mice, where depleting CD8(+) T cells lead to increase severity of disease. Unlike control MHC class II(-/-) mice, the group depleted of CD8(+) T cells developed skin lesions on the tail and feet and had adrenal necrosis. Adoptive transfer experiments also show CD8(+) T cells can mediate protective memory. These results collectively show that both CD4(+) and CD8(+) T cell-mediated immunity can contribute to protection against VV infection. However, CD4(+) T cell-dependent anti-virus Ab production plays a more important role in clearing virus following acute infection, while in the absence of Ab, CD8(+) T cells can contribute to protection against disease.
This paper attempts to summarize current knowledge about immune responses to vaccines that correlate with protection. Although
the immune system is redundant, almost all current vaccines work through antibodies in serum or on mucosa that block infection
or bacteremia/viremia and thus provide a correlate of protection. The functional characteristics of antibodies, as well as
quantity, are important. Antibody may be highly correlated with protection or synergistic with other functions. Immune memory
is a critical correlate: effector memory for short-incubation diseases and central memory for long-incubation diseases. Cellular
immunity acts to kill or suppress intracellular pathogens and may also synergize with antibody. For some vaccines, we have
no true correlates, but only useful surrogates, for an unknown protective response.
The author has determined the antitoxin-titer of 425 patients with clinical manifest diphtheria faucium. Of these, 287 were unvaccinated, 32 vaccinated once and 106 vaccinated with more than one injection.
In the case of the vaccinated the course of the disease was distinctly milder than that of the unvaccinated, while at the same time the antitoxin titre was much higher for the former than for the latter.
When the unvaccinated are divided into groups according to the severity of the disease, there is only a slight difference in the antitoxin-titers of the groups.
When all the cases are grouped according to the antitoxin-titer there is a scarcely demonstrable difference in the course of the disease for groups with a high titer and those with a low titer, provided that the course is indicated by means of the relative occurrence of complications and deaths in the groups.
When a comparison is made between the distribution of antitoxin-titer among diphtherics and distributions among the rest of the population, there are found to be fewer cases of a titer higher than 0.1 A.U. among the diphtherics.
The material is further treated statistically, the author having found a single quantity as an indicator for the course of the disease for each patient. The average course of each group can then be computed as the mean of the course of the individual cases. This provides greater statistical certainty than an analysis of the percentage of complications.
It was then possible to show a significant dependence between antitoxin-titer and course of disease, although the slope of the regression found was rather flat.
The vaccinated patients had a better course of illness than the unvaccinated who presented the same clinical picture on hospitalization and had the same initial antitoxin-titer.
An obstacle to developing a successful rotavirus vaccine has been the inability to consistently correlate the humoral immune
response with protection against disease. Transplacental transfer of maternal rotavirus-specificantibodies may obscure the
capacity to discriminate an active from a passively acquired humoral immune response in infants. In an attempt to circumvent
this problem, an assay was developed to detect rotavirus-specific helper T cells among circulating mononuclear cells. Rotavirus-specificlymphoproliferative
responses and rotavirus-specificneutralizing antibody titers in blood were determined in 11 mother/newborn pairs at the time
of deliveryand in 54 infants, children, and adults ranging in age from 16 days to 40 years. Only 1 of 11 infants tested between
16 days and 6 months of age had detectable rotavirus-specifichelper T cell activity whereas 8 of 11 had circulating rotavirus-specific
neutralizing antibodies. Acquisition of rotavirus-specific helper T cell activity over the first fewyears of life correlated
with the age at which infants and young children are known to be infected with rotavirus. These findings support the hypothesis
that detection of rotavirus-specificlymphoproliferative activity in infants may more accurately determine previous exposure
to rotavirus than detection of rotavirus-specifie antibodies.
CD4+ T-cell lines with specificity for individual measles virus (MV) structural proteins were obtained from immunized Lewis rats. Isolated viral proteins, either purified from virions or bacterially expressed were used as antigens for immunological assays. All the cell lines secreted interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), but were only weakly cytotoxic to autologous MV-infected astrocytes. When cultured together with memory splenic B lymphocytes these T cells did not induce secretion of MV-specific antibodies. The in vivo function of the T-cell lines was investigated in our MV-encephalitis model in the Lewis rat. Within 24 hr of intracerebral infection, adoptive transfer of single MV protein-specific T cells either decreased or prevented the subsequent clinical and histological disease depending on the MV-protein specificity of the cell lines. Furthermore, there was an earlier and enhanced viral clearance from the CNS, without a change in the anti-MV antibody titres of serum and cerebrospinal fluid (CSF) of the recipients and the control-infected animals. Prior depletion of CD8+ T lymphocytes in the recipient animals did not abrogate the protection conferred by CD4+ T-cell lines, indicating that the acute viral CNS disease is being efficiently controlled by virus-specific CD4+ T cells.
Oral poliovaccine (OPV) is recommended for routine immunization in the United States in part because of its ability to induce
intestinal and pharyngeal immunity to reinfection, Mucosal immunity produced by OPV and enhanced-potency inactivated poliovaccine
(E-IPV) was compared bychallenging vaccinees with type 1 OPV, Fewer OPV (25%) than E-IPV(63%) vaccinees excreted OPV virus
in stool after challenge. The mean stool virus titer was higher and the duration of shedding longer among E-IPV excreters.
Only one E-IPV and three OPV vaccinees shed virus in the pharynx after challenge. Prechallenge serum neutralizing antibody
levels were not statistically different among E-IPV vaccinees whodid and did not shed virus; these levels were much higher
than those of OPV vaccinees. Poliovirus-specific 19A levels in stool did not correlate with viral excretion. E-IPV was less
effective that OPV in preventing and limiting intestinal infection, even though it induced higher post vaccination serum antibody
levels.
To test the protective effect of Towne live attenuated human cytomegalovirus (HCMV) Vaccine in normal individuals, we developed
a parenteral challenge consisting of a low-passage isolate (Toledo stain) inoculated subcutaneouslyin graded doses. This challenge
virus caused a mild mononucleosis syndrome in seronegative individuals at doses of 10 or 100 pfu. The illness was accompanied
by atypical lymphocytosis, raised hepatic enzymes, excretion of HCMV and HCMV-specific immune responses. Naturally seropositive
volunteers also developed clinical and laboratory evidence of infection after challenge with 1,000 pfu of Toledo but resisted
10 or 100 pfu. Volunteers who had been vaccinated 1 y earlier also were resistant to disease caused by 10 or 100 pfu of Toledo,
although some were asymptomatically infected by the 100 pfu dose. Vaccine-induced immunity to HCMV was as complete as naturally
induced immunity when the challenge dose of Toledo was 10 pfu.
The intranasal inoculation of volunteers with living partially attenuated strains of influenza A and B viruses offers a new opportunity to determine the protective effect of serum haemagglutin-inhibiting antibody against a strictly homologous virus, under conditions where the time and dosage of the infective challenge can be controlled, the scoring of proven infections can be more precise and higher rates of infection can be achieved than in most natural epidemics.
In 1032 adult volunteers, whose serum HI antibody titre was determined immediately before virus challenge, there was a consistent inverse quantitative relationship between the HI titre and the likelihood of infection. The PD50 (50 % protective dose) of HI antibody was 1/18–1/36, but an unusual finding was that volunteers with no detectable pre-challenge antibody often seem to be less susceptible to infection than those with pre-challenge antibody in low titre.
In one group of volunteers challenged with an influenza B strain there was no evidence that pre-challenge antibody titres against viral neuraminidase had any significant protective effect against challenge infection.
Pre- and postexposure prophylaxis against hepatitis A virus (HAV) infection with immune serum globulin (Ig) is only effective for 4-6 months. We compared the safety, tolerability and immunogenicity of a single i.m. injection of Ig with a single and booster dose of an inactivated hepatitis A virus vaccine (iHAV) in adults. Healthy volunteers (18-50 years) received a single Ig i.m. injection (n = 30), or iHAV i.m. (n = 15) at 0 and 24 weeks, or placebo (n = 4) at the same intervals. Anti-HAV seroconversion was measured by radioimmunoassay (RIA) and neutralizing antibodies by an antigen reduction assay. After Ig injection (0.06 ml/kg), anti-HAV seroconversion occurred in 100% of recipients at week 1, declining to 10% at week 12 and 0% by week 20. In contrast, after a single 25 ng dose, RIA seropositivity in iHAV vaccinees was 80% by week 2, reaching 100% by week 5 and persisted up to week 24, at which time anti-HAV geometric mean titres (GMT) were two fold higher than those seen at week 1 after Ig. Postbooster anti-HAV titres in iHAV recipients rose within 4 weeks to 73-fold greater than the peak GMT seen one week after Ig, and 400-fold higher than GMT at 12 weeks after Ig. Neutralizing antibody titres after iHAV followed a similar pattern, as observed for anti-HAV. iHAV was well tolerated; placebo and vaccine tolerability were indistinguishable, with no serious adverse experiences observed. In conclusion, active vaccination with a single iHAV dose may eventually replace Ig for pre-exposure prophylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)
The Rubella Subcommittee of the National Committee for Clinical Laboratory Standards has proposed lowering the breakpoint to define rubella immunity from 15 to 10 IU/mL. This recommendation stems from epidemiologic studies on vaccinated persons with low levels of antibody and anecdotal reports. Additional support comes from Centers for Disease Control and Prevention studies and reports. The effectiveness of rubella vaccination is well documented and the 10 IU/mL antibody level is protective in the vast majority of persons. Sporadic reports of viremia and/or reinfection among previously immunized persons with low antibody levels have been reported but proven cases of reinfection have also occurred in persons with titers greater than or equal to the 15 IU/mL cut-off. Despite the occasional occurrence of rubella reinfection in persons with low titers, the theoretical risks are small especially as compared with significantly greater risk in persons who have not been vaccinated. Immunity in a given patient is a clinical decision and the results of antibody tests for rubella, like other laboratory tests, must be evaluated in the context of the clinical setting.
Varicella vaccine in immunocompromised children was clinically evaluated in 575 US and Canadian children with leukemia in
remission by the Varicella Vaccine Collaborative Study. Most children had chemotherapy stopped 1 week before and 1 week after
immunization. Steroids were stopped for 3 weeks (l week before to 2 weeks after vaccination). Varicella vaccine was safe,
immunogenic, and effective in leukemic children at risk for serious disease or death from chickenpox. The major side effect
was mild rash in 50% ∼ 1 month after immunization. About 40% of children who developed rash were treated with acyclovir. Vaccine
efficacy was judged by the degree of protection after a household exposure to varicella; of 123 exposed children, 17 (14%)
developed a mild form of varicella. The vaccine protected completely against severe varicella. Leukemic vaccinees were less
likely to develop zoster than were comparable children with leukemia who had wild type varicella. Thus, varicella vaccine,
administered carefully with close follow-up, is extremely beneficial for leukemic children.
A comparison was made of antibody responses generated to live varicella (Oka/Merck) vaccine (Varivax) produced during three different manufacturing campaigns to evaluate the quality of the antibody responses and demonstrate consistency of the manufacturing process. Anti-varicella zoster virus (VZV) antibody titers were measured by an enhanced neutralization assay and VZV glycoprotein-based enzyme-linked immunosorbent assay (gpELISA). For sera taken from children who had received one dose of vaccine an excellent linear concordance in titers was observed between the two assays. Sera from adults who had received two doses demonstrated continuing increased neutralization at high gpELISA titers. The immunogenicity measured by the two assays demonstrates that the overall performance of the vaccine was very similar over the three production series.
To define the concentration of anti-rubella virus (RV) antibodies discriminating nonimmune from immune persons and to characterize
immune responses to rubella vaccination, serologic studies were performed after rubella vaccination in persons with low or
undetectable antibody concentrations. Thirty-six subjects with primary immune responses had prevaccination anti-RV IgG concentrations
<15 IU/mL by ELISA and negative results by radial hemolysis. Eighty-three subjects with secondary immune responses had mean
IgG increases of 9 IU/mL within 2 weeks. Eight of them had initial IgG levels <15 IU/mL, and 2 were negative by radial hemolysis.
Both groups attained similar antibody levels after 1–3 months. Secondary immune responses to rubella vaccination were delayed
by >2 weeks and thus resembled the time course of primary immunization, but IgM responses and IgG avidity were distinct between
subjects with primary or secondary immune responses. Thresholds for immunity <15 IU/mL entail the risk of withholding rubella
vaccination from susceptible persons.
Neisseria meningitidis serogroup C bactericidal titers and class-specific enzyme-linked immunosorbent assay (ELISA) antibody concentrations were measured in sera from 173 children (1 to 5 years old) before and 6 weeks and 7 months following vaccination with a quadrivalent (A/C/Y/W-135) polysaccharide vaccine. The immune responses of the children were compared with those of 40 adults 6 weeks postvaccination. Both bactericidal titers and ELISA antibody concentrations were significantly higher in the adults than in the children (P < 0.05). In addition, the ratio of immunoglobulin G (IgG) to IgM was higher in the children than in the adults. With an ELISA total antibody concentration of >/=2 microg/ml used as a measure of seroconversion, >/=84% of the individuals from each age group responded to the serogroup C polysaccharide. However, with a >/=4-fold-increase in bactericidal titer used, only 18% of 1-year-olds, 32% of 2-year-olds, and 50 to 60% of 3-, 4-, and 5-year-olds seroconverted. The ELISA results suggest that >50% of all children retained >/=2 microg of total antibody per ml at 7 months postimmunization. However, the bactericidal titers suggest that <10% of children <4 years old retained a >/=4-fold increase at 7 months following vaccination. Of particular note, 59 of 79 sera (75%) from the 1- and 2-year-olds had high ELISA antibody concentrations (2 to 20 microg/ml) with no associated bactericidal titer (<1:8). Discordant results between bactericidal titers and ELISA antibody concentrations were not explained by the presence of IgA blocking antibody or relative levels of IgG and IgM. The bactericidal results show age-dependent differences in the production and retention of antibody in young children immunized with serogroup C polysaccharide; these differences are not evident with the ELISA data.
Vaccine efficacies against typical pertussis after household exposure to Bordetella pertussis were estimated to be 75.4% for an acellular five-component vaccine, 42.4% for an acellular two-component vaccine, and 28.5%, for a licensed US whole cell vaccine, compared to placebo. Logistic regression analyses demonstrated statistically significant correlations between clinical protection and the presence of IgG antibodies against pertactin, fimbriae 2/3 and pertussis toxin in pre-exposure sera. Multicomponent pertussis vaccines of proven high efficacy in recent Swedish NIAID-sponsored efficacy trials induced higher antibody levels against pertactin and fimbriae 2/3 than less efficacious vaccines. Anti-pertactin, anti-fimbriae 2/3, and anti-PT may be used as surrogate markers of protection for multicomponent acellular and whole-cell vaccines against pertussis.
In a pertussis vaccine efficacy trial in Germany we collected sera from vaccinees (DTaP or DTP) after the third and fourth doses of vaccine or at comparable time periods in DT vaccine recipients. In addition, sera were collected from a randomized sample of subjects in each vaccine group at approximately 3-month intervals from which antibody kinetic curves were constructed, which allowed us to estimate specific antibody values to pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin and fimbriae-2 at the time of exposure in the household setting. The imputed geometric mean antibody values to PT, pertactin and fimbriae-2 at the time of household exposure to Bordetella pertussis infection were higher (p < 0.07 or lower) in non-cases compared with cases. A multivariate (classification tree) analysis found that only pertactin and PT were significant in protection. Subjects with an imputed pertactin value of < 7 EU ml-1 had a 67% (18/27) chance of infection regardless of the PT value. If the pertactin value was > or = 7 EU ml-1 and the PT value > or = 66 EU ml-1 all subjects were non-cases. If the pertactin value was > or = 7 and the PT value was < 66 EU ml-1 the predicted probability of being a case was 31% (15/49). Logistic regression analysis also found that high versus low pertactin values were associated with illness prevention following household exposure. In the presence of antibody to pertactin, PT and fimbriae-2, the additional presence of antibody to FHA did not contribute to protection. Our data support historical data indicating that agglutinating antibodies are associated with protection and also recent serologic correlates data and clinical efficacy data which indicate that multicomponent vaccines containing pertactin and fimbriae have better efficacy than PT or PT/FHA vaccines.
The incidence of anthrax in humans is extremely low. Human vaccine efficacy studies for inhalational anthrax cannot be conducted. The identification of a correlate of protection that predicts vaccine efficacy is crucial for determining the immune status of immunized humans. This surrogate marker of immunity can only be established by using an appropriate animal model. Numerous studies showed that protective antigen (PA) is the principle protective antigen in naturally- or vaccine-induced immunity. However, attempts to correlate the quantity of anti-PA antibodies with protective immunity in the guinea pig model for anthrax and various vaccine formulations have failed. In these studies, we used the licensed anthrax vaccine adsorbed (AVA) in rabbits.
The reputation of vaccination rests on a 200-year-old history of success against major infectious diseases. That success has led to the doctrine of 'for each disease, a vaccine'. Although some diseases have proved frustrating, this doctrine carries considerable truth. However, when one reviews the vaccines now available it is apparent that most successes have been obtained when the microbe has a bacteremic or viremic phase during which it is susceptible to the action of neutralizing antibodies, and before replication in the particular organ to which it is tropic. Poliomyelitis and infections by capsulated bacteria are examples where vaccination has worked efficiently. However, some success has also been achieved against agents replicating on respiratory or gastrointestinal mucosae. Influenza, pertussis and rotavirus vaccines are examples of such agents, against which it has been possible to induce immune responses acting locally as well as systemically. In addition, when bacteria produce disease through exotoxins, purification and chemical or genetic inactivation of those toxins has yielded highly efficacious vaccines. Control of intracellular pathogens has not been achieved, except partly with the BCG vaccine against tuberculosis, and modern efforts are directed towards pathogens against which cellular immune responses are critical. In general, two achievements have been crucial to the success of vaccines: the induction of long-lasting immunological memory in individuals and the stimulation of a herd immunity that enhances control of infectious diseases in populations.
A current debate is whether the immunologic priming of infants with Haemophilus influenzae type b (Hib) conjugate vaccines would be protective in the absence of circulating antibody to the capsular polysaccharide (PS). Data from the prevaccine era on the PS antibody responses of older children to Hib meningitis may be informative on this issue.
PS antibody was assayed by radioantigen binding in sera taken in the first month postadmission in 47 children ages 2 to 136 months with culture-proved Hib meningitis.
Sera obtained on admission had very low antibody concentrations, and the subsequent response during convalescence was age-dependent. The major finding is that some patients, including 10 of 11 children older than 2 years, had substantial antibody elevations within a few days of admission, increases resembling the response to PS vaccine in infants primed with PS-protein conjugate vaccines.
In this group of patients with Hib meningitis, natural priming did not prevent infection. Hib may have the ability to invade despite the capacity for a vigorous antibody response.