Article

Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19)

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  • Janssen Vaccines & Prevention
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Abstract

Background: More than 1·8 million new cases of HIV-1 infection were diagnosed worldwide in 2016. No licensed prophylactic HIV-1 vaccine exists. A major limitation to date has been the lack of direct comparability between clinical trials and preclinical studies. We aimed to evaluate mosaic adenovirus serotype 26 (Ad26)-based HIV-1 vaccine candidates in parallel studies in humans and rhesus monkeys to define the optimal vaccine regimen to advance into clinical efficacy trials. Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled phase 1/2a trial (APPROACH). Participants were recruited from 12 clinics in east Africa, South Africa, Thailand, and the USA. We included healthy, HIV-1-uninfected participants (aged 18-50 years) who were considered at low risk for HIV-1 infection. We randomly assigned participants to one of eight study groups, stratified by region. Participants and investigators were blinded to the treatment allocation throughout the study. We primed participants at weeks 0 and 12 with Ad26.Mos.HIV (5 × 1010 viral particles per 0·5 mL) expressing mosaic HIV-1 envelope (Env)/Gag/Pol antigens and gave boosters at weeks 24 and 48 with Ad26.Mos.HIV or modified vaccinia Ankara (MVA; 108 plaque-forming units per 0·5 mL) vectors with or without high-dose (250 μg) or low-dose (50 μg) aluminium adjuvanted clade C Env gp140 protein. Those in the control group received 0·9% saline. All study interventions were administered intramuscularly. Primary endpoints were safety and tolerability of the vaccine regimens and Env-specific binding antibody responses at week 28. Safety and immunogenicity were also assessed at week 52. All participants who received at least one vaccine dose or placebo were included in the safety analysis; immunogenicity was analysed using the per-protocol population. We also did a parallel study in rhesus monkeys (NHP 13-19) to assess the immunogenicity and protective efficacy of these vaccine regimens against a series of six repetitive, heterologous, intrarectal challenges with a rhesus peripheral blood mononuclear cell-derived challenge stock of simian-human immunodeficiency virus (SHIV-SF162P3). The APPROACH trial is registered with ClinicalTrials.gov, number NCT02315703. Findings: Between Feb 24, 2015, and Oct 16, 2015, we randomly assigned 393 participants to receive at least one dose of study vaccine or placebo in the APPROACH trial. All vaccine regimens demonstrated favourable safety and tolerability. The most commonly reported solicited local adverse event was mild-to-moderate pain at the injection site (varying from 69% to 88% between the different active groups vs 49% in the placebo group). Five (1%) of 393 participants reported at least one grade 3 adverse event considered related to the vaccines: abdominal pain and diarrhoea (in the same participant), increased aspartate aminotransferase, postural dizziness, back pain, and malaise. The mosaic Ad26/Ad26 plus high-dose gp140 boost vaccine was the most immunogenic in humans; it elicited Env-specific binding antibody responses (100%) and antibody-dependent cellular phagocytosis responses (80%) at week 52, and T-cell responses at week 50 (83%). We also randomly assigned 72 rhesus monkeys to receive one of five different vaccine regimens or placebo in the NHP 13-19 study. Ad26/Ad26 plus gp140 boost induced similar magnitude, durability, and phenotype of immune responses in rhesus monkeys as compared with humans and afforded 67% protection against acquisition of SHIV-SF162P3 infection (two-sided Fisher's exact test p=0·007). Env-specific ELISA and enzyme-linked immunospot assay responses were the principal immune correlates of protection against SHIV challenge in monkeys. Interpretation: The mosaic Ad26/Ad26 plus gp140 HIV-1 vaccine induced comparable and robust immune responses in humans and rhesus monkeys, and it provided significant protection against repetitive heterologous SHIV challenges in rhesus monkeys. This vaccine concept is currently being evaluated in a phase 2b clinical efficacy study in sub-Saharan Africa (NCT03060629). Funding: Janssen Vaccines & Prevention BV, National Institutes of Health, Ragon Institute of MGH, MIT and Harvard, Henry M Jackson Foundation for the Advancement of Military Medicine, US Department of Defense, and International AIDS Vaccine Initiative.

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... Compared to natural occurring antigens, the mosaic proteins mediated the enhanced T cell epitope recognition of CD8 + and CD4 + T cells and the cross-recognition of variants of these epitopes [209][210][211]. Encouraged by these promising results, an adenovirus serotype 26 (Ad26) vectored vaccine Ad26.Mos.HIV (consisting of Ad26.Mos.1.Env, Ad26.Mos1.Gag-Pol, Ad26.Mos2.Gag-Pol), a modified vaccinia Ankara (MVA)-Mosaic vaccine (MVA.Mos.1.Env, MVA.Mos1.Gag-Pol, MVA.Mos2.Gag-Pol) and a subsequent protein boost with adjuvanted clade C gp140 proteins (truncated Env precursors) were tested in a clinical trial (APPROACH) and a rhesus monkey challenge study [212]. The envelope glycoproteins were either applied in a membrane-anchored form displayed on the surfaces of Ad26.Mos.1.Env transduced cells or as soluble gp140 proteins used for boosting. ...
... In summary, the vaccine regimen was highly immunogenic in humans and in primates alike. A 67% protection against infection with a Simian-Human Immunodeficiency Virus (SHIV)-SF162P3) was achieved when rhesus monkeys were subjected to six intrarectal virus challenges, raising hopes for the desired potency in humans [212]. ...
... In 2017, the vaccine components of the APPROACH study were further used in an efficacy trial in Southern Africa under the study name Imbokodo [212,215]. Imbokodo enrolled 2637 participants in a phase IIb clinical trial. However, the Imbokodo study was recently terminated ahead of schedule due to disappointing efficacy [216]. ...
Article
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Different mechanisms mediate the toxicity of RNA. Genomic retroviral mRNA hijacks infected host cell factors to enable virus replication. The viral genomic RNA of the human immunodeficiency virus (HIV) encompasses nine genes encoding in less than 10 kb all proteins needed for replication in susceptible host cells. To do so, the genomic RNA undergoes complex alternative splicing to facilitate the synthesis of the structural, accessory, and regulatory proteins. However, HIV strongly relies on the host cell machinery recruiting cellular factors to complete its replication cycle. Antiretroviral therapy (ART) targets different steps in the cycle, preventing disease progression to the acquired immunodeficiency syndrome (AIDS). The comprehension of the host immune system interaction with the virus has fostered the development of a variety of vaccine platforms. Despite encouraging provisional results in vaccine trials, no effective vaccine has been developed, yet. However, novel promising vaccine platforms are currently under investigation.
... This Phase 1/2 trial assessed seven regimens containing Ad26 or MVA vectors expressing mosaic antigens, with some groups boosted with high or low doses of gp140 adsorbed to aluminium phosphate. All regimens were safe and well tolerated [65], and binding antibody responses to autologous clade C gp140 was detected in all groups following the second prime immunization at month 3. After the first boost immunization at month 6, most groups maintained 100% antibody response. ...
... In comparison to the gp140-only group, the inclusion of either Ad26.Mos.HIV or MVA-mosaic increased responses. The utility of the mosaic antigens was demonstrated by the ability to elicit binding IgG responses to crossclade transmitted/founder Envs, Envs isolated from chronically infected individuals, and to consensus sequence Envs that were similar to the vaccine homologous responses [65]. Similar to RV144 vaccinees, a substantial number of subjects showed responses to gp70-V1V2 antigens and the IgG subclasses elicited were IgG1 and IgG3. ...
... The highest ADCP responses were observed in the gp140-boosted groups, particularly those primed with a viral vector. Serum neutralizing activity was only detected against tier-1HIV variants [65]. ...
Article
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Introduction The development of an effective vaccine to protect against HIV is a longstanding global health need complicated by challenges inherent to HIV biology and to the execution of vaccine efficacy testing in the context of evolving biomedical prevention interventions. This review describes lessons learnt from previous efficacy trials, highlights unanswered questions, and surveys new approaches in vaccine development addressing these gaps. Methods We conducted a targeted peer-reviewed literature search of articles and conference abstracts from 1989 through 2021 for HIV vaccine studies and clinical trials. The US National Library of Medicine's Clinical Trials database was accessed to further identify clinical trials involving HIV vaccines. The content of the review was also informed by the authors’ own experience and engagement with collaborators in HIV vaccine research. Discussion The HIV vaccine field has successfully developed multiple vaccine platforms through advanced clinical studies; however, the modest efficacy signal of the RV144 Thai trial remains the only demonstration of HIV vaccine protection in humans. Current vaccine strategies include prime-boost strategies to improve elicitation of immune correlates derived from RV144, combination mosaic antigens, novel viral vectors, antigens designed to elicit broadly neutralizing antibody, new nucleic acid platforms and potent adjuvants to enhance immunogenicity across multiple classes of emerging vaccine candidates. Conclusions HIV vaccine developers have applied lessons learnt from previous successes and failures to innovative vaccine design approaches. These strategies have yielded novel mosaic antigen constructs now in efficacy testing, produced a diverse pipeline of early-stage immunogens and novel adjuvants, and advanced the field towards a globally effective HIV vaccine.
... These immunogens have the maximum of potential T cell epitopes and, if administered as a vaccine, induce broader cellular and humoral immune responses as compared to wild-type of consensus HIV-1 antigens [27]. In theory, mosaic antigens could generate a global HIV-1 vaccine [28]. A phase I clinical trial testing mosaic Env and Gag-pol antigen set in adenovirus serotype 26 proved that the vaccine induced strong Env-specific immune responses in the bloodstream and colorectal mucosa [28]. ...
... In theory, mosaic antigens could generate a global HIV-1 vaccine [28]. A phase I clinical trial testing mosaic Env and Gag-pol antigen set in adenovirus serotype 26 proved that the vaccine induced strong Env-specific immune responses in the bloodstream and colorectal mucosa [28]. ...
... Barouch et al. found that Env-specific binding antibody responses, antibody-dependent cellular phagocytosis responses, and T-cell responses were present in 100%, 80%, and 83% of participants. This research group also administered a similar vaccine regimen in rhesus monkeys and found that it provided a 66% protection against SHIV-SF16P3 infection in six virus challenges [28]. While this is an exciting development, it is important to note that the virus challenges consisted of one strain and the mosaic vaccine may not be able to protect against different strains [27]. ...
Article
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HIV-1 infection and its progression to AIDS remains a significant global health challenge, particularly for low-income countries. Developing a vaccine to prevent HIV-1 infections has proven to be immensely challenging with complex biological acquisition and infection, unforeseen clinical trial disappointments, and funding issues. This paper discusses important landmarks of progress in HIV-1 vaccine development, various vaccine strategies, and clinical trials.
... Adenovirus vector vaccines, carrying HIV-1 or SIV genes, including env with Env protein boosting, have provided significant protection from acquisition in some macaque experiments (4,31,40). The protection was largely attributed to non-NAbs, with support from a macaque challenge study of passive immunization with IgG purified from vaccinated animals that had immune signatures associated with protection (31). ...
... The protection was largely attributed to non-NAbs, with support from a macaque challenge study of passive immunization with IgG purified from vaccinated animals that had immune signatures associated with protection (31). However, when humans were immunized with similar adenovirus-based vaccines before Env protein boosting, they were not protected from infection (HVTN 705/HPX2008) (Table 1) (4,41). ...
... It has remained unexplained why a subset of non-NAbs to V2 would distinguish themselves from the others and how they would uniquely confer protection. To avoid future disappointments, if any CoP candidates are identified in more recent efficacy trials they should be thoroughly validated as effective mCoPs experimentally before forming the basis of new vaccine strategies (4,41,59,62,63) (Table 1). ...
Article
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With the much-debated exception of the modestly reduced acquisition reported for the RV144 efficacy trial, HIV-1 vaccines have not protected humans against infection, and a vaccine of similar design to that tested in RV144 was not protective in a later trial, HVTN 702. Similar vaccine regimens have also not consistently protected nonhuman primates (NHPs) against viral acquisition. Conversely, experimental vaccines of different designs have protected macaques from viral challenges but then failed to protect humans, while many other HIV-1 vaccine candidates have not protected NHPs. While efficacy varies more in NHPs than humans, vaccines have failed to protect in the most stringent NHP model. Intense investigations have aimed to identify correlates of protection (CoPs), even in the absence of net protection. Unvaccinated animals and humans vary vastly in their susceptibility to infection and in their innate and adaptive responses to the vaccines; hence, merely statistical associations with factors that do not protect are easily found. Systems biological analyses, including artificial intelligence, have identified numerous candidate CoPs but with no clear consistency within or between species. Proposed CoPs sometimes have only tenuous mechanistic connections to immune protection. In contrast, neutralizing antibodies (NAbs) are a central mechanistic CoP for vaccines that succeed against other viruses, including SARS-CoV-2. No HIV-1 vaccine candidate has yet elicited potent and broadly active NAbs in NHPs or humans, but narrow-specificity NAbs against the HIV-1 isolate corresponding to the immunogen do protect against infection by the autologous virus. Here, we analyze why so many HIV-1 vaccines have failed, summarize the outcomes of vaccination in NHPs and humans, and discuss the value and pitfalls of hunting for CoPs other than NAbs. We contrast the failure to find a consistent CoP for HIV-1 vaccines with the identification of NAbs as the principal CoP for SARS-CoV-2.
... 8,9 Other Ad26based vaccines, including an approved Ebola vaccine, are safe and have induced durable immune responses. 8,[10][11][12][13] Ad26.COV2.S induced durable protection at low doses in preclinical SARS-CoV-2 challenge studies, 8,14 and initial clinical data showed that a single dose at 5×10 10 viral particles was safe and induced excellent humoral and cellular immune responses. 9 Ad26.COV2.S can be stored for up to 2 years in a standard freezer and up to 3 months at refrigerator temperatures, which simplifies transport, storage, and use in a pandemic. ...
... Data from the current trial are supported by long-term and robust safety data on the Ad26 platform. [10][11][12] A key strength of this trial is that it showed vaccine efficacy in an ethnically and geographically diverse population, including participants in regions with emerging SARS-CoV-2 variants, as well as in participants with coexisting conditions that have been associated with an increased risk of severe Covid-19. A limitation of the trial is the relatively short follow-up, which was necessitated, as in other Covid-19 vaccine trials, by the urgent need for vaccine. ...
Article
The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a prefusion-stabilized conformation. METHODS In an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×1010 viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe–critical coronavirus disease 2019 (Covid-19) with an onset at least 14 days and at least 28 days after administration among participants in the per-protocol population who had tested negative for SARS-CoV-2. Safety was also assessed. RESULTS The per-protocol population included 19,630 SARS-CoV-2–negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe–critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval [CI], 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe–critical Covid-19 (76.7% [adjusted 95% CI, 54.6 to 89.1] for onset at ≥14 days and 85.4% [adjusted 95% CI, 54.2 to 96.9] for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe–critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe– critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19–related), and 16 in the placebo group (5 were Covid-19–related). CONCLUSIONS A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe–critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others;
... Vectoring with Ad26, a non-replicating adenovirus, conferred partial protection against acquisition of infection against SHIV-SF162p3 or SIVmac251 in non-human primates (NHPs) when used in prime followed by protein boosts 5,6 . Tested in phase I/IIa trials, this vaccine candidate has been shown to be safe and immunogenic 7 . Currently, this vaccine approach is undergoing two phase 2b-3 clinical evaluations in South Africa (HVTN 705) and the United States (MOSAICO) 8 . ...
... Vaccine protection against SHIV-SF162p3 resistance to neutralization has been achieved only in a limited number of NHP trials 6,7,42,43 . CCR5-tropic SHIV-SF162p3 is a stringent NHP challenge model that induces a very low level of neutralizing antibody in long-term-infected NHP 49 . ...
Article
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Replicative vectors derived from live-attenuated measles virus (MV) carrying additional non-measles vaccine antigens have long demonstrated safety and immunogenicity in humans despite pre-existing immunity to measles. Here, we report the vaccination of cynomolgus macaques with MV replicative vectors expressing simian-human immunodeficiency virus Gag, Env, and Nef antigens (MV-SHIV Wt) either wild type or mutated in the immunosuppressive (IS) domains of Nef and Env antigens (MV-SHIV Mt). We found that the inactivation of Nef and Env IS domains by targeted mutations led to the induction of significantly enhanced post-prime cellular immune responses. After repeated challenges with low doses of SHIV-SF162p3, vaccinees were protected against high viremia, resulting in a 2-Log reduction in peak viremia, accelerated viral clearance, and a decrease -even complete protection for nearly half of the monkeys- in reservoir cell infection. This study demonstrates the potential of a replicative viral vector derived from the safe and widely used measles vaccine in the development of a future human vaccine against HIV-1.
... Unfortunately, after the advancement to a phase 2b/3 trial, HVTN 702, the interim analysis determined that there was no significant difference between infection rates of those vaccinated and thus determined inefficacious [526]. A third vaccine strategy is the use of mosaic vaccines which are focusing on eliciting a CD8 + T-cell-mediated control [527,528]. These vaccines use mosaic proteins, polyvalent antigens formed from peptides of natural sequences determined by computer modeling for the optimal coverage of epitopes [529]. ...
... A phase I/IIa clinical trial found that the mosaic Ad26 prime with Ad26 + gp140 boost vaccine regimen was highly immunogenic, eliciting strong binding antibody responses, antibody-dependent cellular phagocytosis responses, and T-cell responses. Further, in RMs they found it produced 66% protection from six SHIV-SF162P3 challenges [528]. This vaccine regimen is now being tested in two clinical trials, HVTN 705 (HPX2008; imbokodo) and HVTN 706 (HPX3002; Mosaico). ...
Article
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HIV infection requires lifelong antiretroviral therapy (ART) to control disease progression. Although ART has greatly extended the life expectancy of persons living with HIV (PWH), PWH nonetheless suffer from an increase in AIDS-related and non-AIDS related comorbidities resulting from HIV pathogenesis. Thus, an HIV cure is imperative to improve the quality of life of PWH. In this review, we discuss the origins of various SIV strains utilized in cure and comorbidity research as well as their respective animal species used. We briefly detail the life cycle of HIV and describe the pathogenesis of HIV/SIV and the integral role of chronic immune activation and inflammation on disease progression and comorbidities, with comparisons between pathogenic infections and nonpathogenic infections that occur in natural hosts of SIVs. We further discuss the various HIV cure strategies being explored with an emphasis on immunological therapies and “shock and kill”.
... Vaccinated animals were also more difficult to infect and did not succumb to infection when compared to unvaccinated macaques [75]. Mosaic HIV vaccines have demonstrated immunogenicity in humans [76,77], suggesting potential for translation to an HCV vaccine. The feasibility of mosaic design of a pan-genotypic HCV vaccine has been demonstrated by in silico analysis, with multivalent mosaic antigens providing the best coverage against diverse HCV isolate sequences [54]. ...
... Finally, beyond uncovering conserved sites, mosaic E1E2 immunogens may also present an approach to the diversity of HCV envelope antigens. While current efforts in the development and testing of mosaic HIV vaccines focus on cell-mediated immunity, they also elicit neutralizing antibodies that target the variable envelope protein of HIV [69,73,77]. Immunization with a mosaic HCV E2 immunogen has shown enhanced immunogenicity in mice, though neutralizing antibodies were not specifically studied [78]. ...
Article
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Thirty years after its discovery, the hepatitis C virus (HCV) remains a leading cause of liver disease worldwide. Given that many countries continue to experience high rates of transmission despite the availability of potent antiviral therapies, an effective vaccine is seen as critical for the elimination of HCV. The recent failure of the first vaccine efficacy trial for the prevention of chronic HCV confirmed suspicions that this virus will be a challenging vaccine target. Here, we examine the published data from this first efficacy trial along with the earlier clinical and pre-clinical studies of the vaccine candidate and then discuss three key research directions expected to be important in ongoing and future HCV vaccine development. These include the following: 1. design of novel immunogens that generate immune responses to genetically diverse HCV genotypes and subtypes, 2. strategies to elicit broadly neutralizing antibodies against envelope glycoproteins in addition to cytotoxic and helper T cell responses, and 3. consideration of the unique immunological status of individuals most at risk for HCV infection, including those who inject drugs, in vaccine platform development and early immunogenicity trials.
... D'ailleurs, de manière intéressante, si les réponses T CD8 + dirigées contre la protéine Env sont généralement associées à une charge virale élevée en phase chronique de l'infection (Kiepiela et al., 2007), la présence de ces réponses chez des individus vaccinés par différents candidats vaccins semble associée à leur protection contre l'infection par le VIH-1 (Barouch et al., 2018;Janes et al., 2017). Pour cela, en plus d'épitopes spécifiques de la protéine Env, je pense qu'il faut se concentrer sur tous les épitopes T CD8 + dont une mutation peut diminuer la capacité réplicative du VIH-1 et inclure des séquences contenant ces résidus dans le vaccin afin d'éviter un échappement à la réponse immunitaire par le VIH-1. ...
... cette même combinaison vaccinale a permis la protection de 77% des macaques contre une infection par un SHIV. De manière intéressante, les réponses humorales et cellulaires dirigées contre l'enveloppe du VIH-1 sont les corrélats de protection trouvés dans cet essai(Barouch et al., 2018).Ces résultats ont permis le récent lancement de deux essais d'efficacité de phase IIb basés sur ce ...
Thesis
Depuis les années 1990, l’ANRS (France Recherche Nord&Sud Sida-HIV hépatites) a mis en place une stratégie de vaccination anti-VIH-1 originale fondée sur l’utilisation de peptides contenant des épitopes T couplés à une molécule lipidique et capables d’induire des réponses poly-épitopiques. Ces lipopeptides ont la particularité d’induire des réponses cellulaires sans nécessiter d’adjuvant via l’activation du TLR2 par l’acide palmitique composant la queue lipidique de ces lipopeptides qui permet également la cross-présentation d’épitopes T CD8+ par les cellules dendritiques. Le candidat vaccin LIPO-5, constitué de 5 longs peptides (Gag 17-35, Gag 253-284, Nef 66-97, Nef 116-145, et Pol 325-355) comportant différents épitopes T CD8+ et CD4+ du VIH-1 de sous-type B couplés en position C-terminale à un acide monopalmitique via une lysine, est utilisé chez l’homme depuis bientôt 20 ans dans différents essais cliniques de phase I et II.Lors de cette thèse, nous nous sommes focalisés sur l’étude des réponses T CD4+ et CD8+ induites par les vaccins lipopeptidiques développés par l’ANRS et plus particulièrement sur le candidat vaccin LIPO-5, utilisé notamment dans les essais prophylactiques ANRS VAC 18 et VRI 01, et les essais thérapeutiques ANRS LIGHT et DALIA. Nous avons identifié et caractérisé les réponses T CD8+ et CD4+ post-vaccinales lors de l’essai DALIA et comparé ces réponses avec celles observées dans différents essais de vaccination thérapeutique et prophylactique menés par l’ANRS, utilisant des lipopeptides associés ou non à d’autres candidats vaccin (ALVAC, MVA et ADN).Nous avons ainsi pu montrer que l’immunodominance de ces réponses n’était pas modifiée entre volontaires sains et patients infectés par le VIH-1. De plus nous avons montré que l’utilisation du candidat vaccin LIPO-5 en « prime » était particulièrement intéressante pour focaliser les réponses vaccinales sur les régions conservées du VIH-1 intégrées dans ce vaccin, et que le LIPO-5 chargé sur des cellules dendritiques induisait une meilleure immunogénicité, confirmant l’intérêt de ce vaccin pour la stratégie de « DC targeting » ex vivo. Enfin, nous avons également montré que la vaccination lipopeptidique permettait l’induction spécifique d’IL-13 par les LT CD4+ et que cette réponse était associée à un faible rebond viral lors de la phase d’interruption de traitement de l’essai ANRS DALIA.Ces résultats sont importants dans la quête de vaccins prophylactiques et thérapeutiques efficaces contre le VIH-1.
... Many T cell vaccine strategies, for example, the use of novel cytomegalovirus (CMV)-, vaccinia-or adenovirus-based vectors [8][9][10][11], prime-boost regimens of various vaccine combinations [12][13][14], or unique immunogen designs such as mosaic antigens to cover diverse pathogen variants [15][16][17][18][19], elicit protective T cell immunity against SIV or simian-human immunodeficiency virus (SHIV) infections in preclinical macaque studies [14]. However, investigation on the mechanisms underlying sustained setpoint viremia suppression by vaccination alone remains incomplete in non-human primate (NHP) models. ...
... Sustained viremia control underlying PD1-based vaccination may involve polyfunctional effector-memory CD8 + T cells for protection. Currently, the most promising AIDS vaccine candidates in conferring sustained viremia control against pathogenic SIV/SHIV infections involved viral-vectored T cell vaccines such as RhCMV-based vaccine [8,9,11], heterologous Ad5/26 adenovirus-based vaccine [10,18,19] and heterologous vaccinia prime and adenovirus boost vaccine [12]. In these studies, protection was encouragingly observed in subgroups of the vaccinated macaques with complex mechanisms involved. ...
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HIV-1 functional cure requires sustained viral suppression without antiretroviral therapy. While effector-memory CD8 ⁺ T lymphocytes are essential for viremia control, few vaccines elicit such cellular immunity that could be potently recalled upon viral infection. Here, we investigated a program death-1 (PD1)-based vaccine by fusion of simian immunodeficiency virus capsid antigen to soluble PD1. Homologous vaccinations suppressed setpoint viremia to undetectable levels in vaccinated macaques following a high-dose intravenous challenge by the pathogenic SHIV SF162P3CN . Poly-functional effector-memory CD8 ⁺ T cells were not only induced after vaccination, but were also recalled upon viral challenge for viremia control as determined by CD8 depletion. Vaccine-induced effector memory CD8 ⁺ subsets displayed high cytotoxicity-related genes by single-cell analysis. Vaccinees with sustained viremia suppression for over two years responded to boost vaccination without viral rebound. These results demonstrated that PD1-based vaccine-induced effector-memory CD8 ⁺ T cells were recalled by AIDS virus infection, providing a potential immunotherapy for functional cure.
... Fc receptors (FcRs) are cell surface proteins that interact with the Fc domains of antibodies to mediate cell signaling and effector functions (1,2). Results of immune correlates analyses for the RV144 and HVTN505 clinical trials and preclinical vaccine studies conducted in rhesus macaques (RMs) have identified associations between non-neutralizing FcR-dependent antiviral activities of antibodies and reduced risk of HIV/SHIV infection or control of viremia (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Among the myriad of potential FcR-dependent effector functions, antibody-dependent phagocytosis (ADP) of HIV-1/SIV envelope (Env) protein or virions has emerged as a unifying correlate of reduced infection risk in several vaccine studies conducted in RMs (3,4,6,8), and in post-hoc analysis of the human HVTN505 HIV-1 vaccine efficacy trial (16). ...
... Numerous vaccine candidates have been tested in RM models and humans, but vaccine studies performed in RMs (8,(63)(64)(65)(66)(67) have historically been inconsistent predictors of outcomes of human trials (68-71) -suggesting the need for a better understanding of comparative biology across these two species. Several vaccine studies performed in preclinical RM models and human clinical trials have identified associations between FcRmediated antibody effector functions and reduced risk of infection (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Among these FcR-mediated effector functions, vaccine elicited ADP activity has recently emerged as a common correlate of reduced infection risk in both species (3,4,6,8,16,54). ...
Article
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Analyses of human clinical HIV-1 vaccine trials and preclinical vaccine studies performed in rhesus macaque (RM) models have identified associations between non-neutralizing Fc Receptor (FcR)-dependent antibody effector functions and reduced risk of infection. Specifically, antibody-dependent phagocytosis (ADP) has emerged as a common correlate of reduced infection risk in multiple RM studies and the human HVTN505 trial. This recurrent finding suggests that antibody responses with the capability to mediate ADP are most likely a desirable component of vaccine responses aimed at protecting against HIV-1 acquisition. As use of RM models is essential for development of the next generation of candidate HIV-1 vaccines, there is a need to determine how effectively ADP activity observed in RMs translates to activity in humans. In this study we compared ADP activity of human and RM monocytes and polymorphonuclear leukocytes (PMN) to bridge this gap in knowledge. We observed considerable variability in the magnitude of monocyte and PMN ADP activity across individual humans and RM that was not dependent on FcR alleles, and only modestly impacted by cell-surface levels of FcRs. Importantly, we found that for both human and RM phagocytes, ADP activity of antibodies targeting the CD4 binding site was greatest when mediated by human IgG3, followed by RM and human IgG1. These results demonstrate that there is functional homology between antibody and FcRs from these two species for ADP. We also used novel RM IgG1 monoclonal antibodies engineered with elongated hinge regions to show that hinge elongation augments RM ADP activity. The RM IgGs with engineered hinge regions can achieve ADP activity comparable to that observed with human IgG3. These novel modified antibodies will have utility in passive immunization studies aimed at defining the role of IgG3 and ADP in protection from virus challenge or control of disease in RM models. Our results contribute to a better translation of human and macaque antibody and FcR biology, and may help to improve testing accuracy and evaluations of future active and passive prevention strategies.
... 31 If a subtypespecific vaccine proves effective in the future, it will also need to be evaluated in other regions where other subtypes and recombinants pre dominate. A variety of approaches are being taken to address HIV diversity, including the use of artificial centralised sequences, such as consensus, ancestral or centreoftree sequences, 32,33 mosaic and polyvalent vac cines, 34 and focusing on conserved or structurally imp ortant regions of HIV. 35,36 Moreover, with ongoing evolution and recombination, an HIV vaccine might need to be changed periodically, like influ enza vaccines. ...
... Vaccination approaches that aim to activate CD8 + T cells benefit from using virus-based platforms, as live viral vectors mimic infection with a virus and therefore generate strong cellular immune responses. Virus-based vectors have been widely studied and are currently being tested in clinical trials for vaccine, gene therapy, and oncolytic uses [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] . Viral vectors are based on either DNA or RNA viruses, which replicate through different mechanisms and therefore have distinct interactions with the immune system. ...
Article
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The precise mechanism by which many virus-based vectors activate immune responses remains unknown. Dendritic cells (DCs) play key roles in priming T cell responses and controlling virus replication, but their functions in generating protective immunity following vaccination with viral vectors are not always well understood. We hypothesized that highly immunogenic viral vectors with identical cell entry pathways but unique replication mechanisms differentially infect and activate DCs to promote antigen presentation and activation of distinctive antigen-specific T cell responses. To evaluate differences in replication mechanisms, we utilized a rhabdovirus vector (vesicular stomatitis virus; VSV) and an alphavirus-rhabdovirus hybrid vector (virus-like vesicles; VLV), which replicates like an alphavirus but enters the cell via the VSV glycoprotein. We found that while virus replication promotes CD8 ⁺ T cell activation by VLV, replication is absolutely required for VSV-induced responses. DC subtypes were differentially infected in vitro with VSV and VLV, and displayed differences in activation following infection that were dependent on vector replication but were independent of interferon receptor signaling. Additionally, the ability of the alphavirus-based vector to generate functional CD8 ⁺ T cells in the absence of replication relied on cDC1 cells. These results highlight the differential activation of DCs following infection with unique viral vectors and indicate potentially discrete roles of DC subtypes in activating the immune response following immunization with vectors that have distinct replication mechanisms.
... The rare adenovirus serotype vectors originated from human or chimpanzee may circumvent such limitation (10). Nevertheless, given their prior experience in the adenovirus vector-based vaccines against Ebola, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and human immunodeficiency virus type I (HIV-1) (11)(12)(13), this strategy is likely to be superior in largescale manufacturing, distribution, and administration of vaccines, which may practically translate into larger accessibility and greater protection at the population level. Furthermore, killed vaccines developed by Sinopharm and Sinovac also demonstrated impressive safety and efficacy profiles in human populations around the world. ...
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The development of a safe and effective vaccine against SARS-CoV-2, the causative agent of pandemic coronavirus disease-2019 (COVID-19), is a global priority. Here, we aim to develop novel SARS-CoV-2 vaccines based on a derivative of less commonly used rare adenovirus serotype AdC68 vector. Three vaccine candidates were constructed expressing either the full-length spike (AdC68-19S) or receptor-binding domain (RBD) with two different signal sequences (AdC68-19RBD and AdC68-19RBDs). Single-dose intramuscular immunization induced robust and sustained binding and neutralizing antibody responses in BALB/c mice up to 40 weeks after immunization, with AdC68-19S being superior to AdC68-19RBD and AdC68-19RBDs. Importantly, immunization with AdC68-19S induced protective immunity against high-dose challenge with live SARS-CoV-2 in a golden Syrian hamster model of SARS-CoV-2 infection. Vaccinated animals demonstrated dramatic decreases in viral RNA copies and infectious virus in the lungs, as well as reduced lung pathology compared to the control animals. Similar protective effects were also found in rhesus macaques. Taken together, these results confirm that AdC68-19S can induce protective immune responses in experimental animals, meriting further development toward a human vaccine against SARS-CoV-2.
... Recombinant viruses-based vaccines, in particular for adenovirus (Ad) vector, represent a promising field to develop the next generation of vaccines against the emerging infectious disease, such as Coronavirus disease 2019 (COVID-19) [1,2], Ebola virus disease [3], acquired immunodeficiency syndrome (AIDS) [4], influenza (FLU) [5], and Zika virus disease [6]. However, Ad vector-induced systematic toxicity, such as hepatotoxicity, systemic inflammation and thrombocytopenia etc., has been regarded as a huge challenge for its clinical application [7,8]. ...
Article
Adenovirus (Ad) has been extensively developed as a gene delivery vector, but the potential side effect caused by systematic immunization remains one major obstacle for its clinical application. Needle-free mucosal immunization with Ad-based vaccine shows advantages but still faces poor mucosal responses. We herein report that the chemical engineering of single live viral-base vaccine effectively modulated the location and pattern of the subsequently elicited immunity. Through precisely assembly of functional materials onto single live Ad particle, the modified virus can entry host cell in a phagocytosis-dependent manner, which is completely distinct from the receptor-mediated entry of native Ad. RNA-Seq data further demonstrated that the modified Ad-induced innate immunity was sharply reshaped via phagocytosis-related pathway, and therefore promoted the activation and mature of antigen presentation cells (APC). Moreover, the functional shell enabled the modified Ad-based vector enhanced muco-adhesion to nasal tissues in mice, and then prolonged resident time onto mucosal surface, leading to the robust mucosal IgA production and T cell immunity at local and even remote mucosal-associated lymphoid tissues. This study demonstrated that vaccine-induced immunity can be well modulated by chemistry engineering, and this method provides the rational design for needle-free mucosa-targeting vaccine against a variety of emerging infectious diseases.
... The HIV regimens were chosen systematically on the basis of a series of primate challenge studies identifying correlates of protection against challenge studies with simianhuman immunodeficiency virus and early phase clinical studies, which showed clinical safety and similar immunogenicity. 9 Should the strategy with Ad26-based vaccine prove successful, the COVID-19 vaccine experience will provide a helpful blueprint for negotiating global rollout under multiple regulatory agencies and phase 4 safety monitoring. ...
... Modified Vaccinia Ankara (MVA) is an attenuated poxviral vector and has been used in vaccine development for a variety of pathogens (28), including HIV (6,29). Multiple MVA-HIV candidate vaccines have been tested in animal models and are at various stages of clinical development as prophylactic and/or therapeutic vaccines (30)(31)(32)(33). Here, we explored the innate immune stimulatory property of MVA vector and show that, like the canary poxviral vector (10), MVA vector induced strong type I IFN expression and production in human innate immune cells through the cGAS-STING pathway. ...
Article
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Recombinant viral vectors represent an important platform for vaccine delivery. Our recent studies have demonstrated distinct innate immune profiles in responding to viral vectors of different families (e.g., adenovirus versus poxvirus): while human Ad5 vector is minimally innate immune stimulatory, the poxviral vector ALVAC induces strong innate response and stimulates type I interferon (IFN) and inflammasome activation. However, the impact of the innate immune signaling on vaccine-induced adaptive immunity in viral vector vaccination is less clear. Here, we show that Modified Vaccinia Ankara (MVA), another poxviral vector, stimulated a type I IFN response in innate immune cells through cGAS-STING. Using MVA-HIV vaccine as a model, we found that type I IFN signaling promoted the generation of humoral immunity in MVA-HIV vaccination in vivo. Following vaccination, type I IFN receptor-knockout (IFNAR1-/-) mice produced significantly lower levels of total and HIV gp120-specific antibodies compared to wild-type (WT) mice. Consistent with the antibody response, a type I IFN signaling deficiency also led to reduced levels of plasma cells and memory-like B cells compared to WT mice. Furthermore, analysis of vaccine-induced CD4 T cells showed that type I IFN signaling also promoted the generation of a vaccine-specific CD4 T-cell response and a T follicular helper (Tfh) response in mice. Together, our data indicate a role for type I IFN signaling in promoting humoral immunity in poxviral vector vaccination. The study suggests that modulating type I IFN and its associated innate immune pathways will likely affect vaccine efficacy. Copyright
... 18 In Africa, historically, there are very few phase I studies, but this is changing with some phase I infectious disease interventional clinical trials reported for antimalarial drugs, 19 Ebola vaccines, 20 and HIV/AIDS vaccines. 21 Although very few phase I cancer clinical trials are reported in Africa (eg, colon cancer phase I studies), 22 have been conducted in Africa indicates that the scientific skills and infrastructure already exists and can be expanded in future. ...
Article
Cancer is now a formidable health care burden in sub-Saharan Africa (SSA) due to lifestyle westernization and longer life expectancy. The exponential increase in cancer incidence coupled with high mortality rate is not comparable with that seen in westernized countries. To address global cancer disparity, globalization of cancer clinical trials to involve sub-Saharan Africa can serve as a platform where innovative targeted therapies can be made available to patients in the environ. In the 2019 African Organization for Research and Training in Cancer (AORTIC) conference held at Maputo, Mozambique, a group of clinical trialists spanning across multiple continents highlighted the opportunities in Africa for the conduct of cancer clinical trials. The secondary purpose of the meeting was to address the belief that Africa was incapable of conducting interventional cancer trials but showed the in-continent strengths, such as available capacities, trained local clinical trialists with clinical trial experiences, clinical trial consortia, local capabilities, mapping out logistics, ethical consideration, political will, real-time benefits of clinical trials to clinical practice, and future directions for trials.
... Importantly, two of the other non-neutralizing trials, HVTN 705 (known as "Imbokodo") and HVTN 706 (known as "Mosaico"), are currently in progress. The Imbokodo trial, conducted in sub-Saharan Africa in heterosexual women, tests a diverse set of four synthetically designed envelope proteins in an Ad26 platform aimed to give an increased breadth of immune response in combination with a subtype C gp140 [9] and is due to be analysed for efficacy in July 2021. Its companion trial, Mosaico, enrolling MSM and transgender persons in South America, Mexico and the United States is halfway enrolled. ...
... Two studies created synthetic genotype 1 sequences through mosaic and ancestral sequence methods [114,148], and were validated for in vivo immunogenicity or T cell stimulation [149,150]. Of note, the mosaic vaccine approach was previously utilized for HIV antigen design [151], and mosaic HIV antigens were found to be immunogenic in a phase 1/2a clinical trial (NCT02315703) and protective against simian-human immunodeficiency virus (SHIV) infection in rhesus macaques [152]. ...
Article
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A hepatitis C virus (HCV) vaccine is a critical yet unfulfilled step in addressing the global disease burden of HCV. While decades of research have led to numerous clinical and pre-clinical vaccine candidates, these efforts have been hindered by factors including HCV antigenic variability and immune evasion. Structure-based and rational vaccine design approaches have capitalized on insights regarding the immune response to HCV and the structures of antibody-bound envelope glycoproteins. Despite successes with other viruses, designing an immunogen based on HCV glycoproteins that can elicit broadly protective immunity against HCV infection is an ongoing challenge. Here, we describe HCV vaccine design approaches where immunogens were selected and optimized through analysis of available structures, identification of conserved epitopes targeted by neutralizing antibodies, or both. Several designs have elicited immune responses against HCV in vivo, revealing correlates of HCV antigen immunogenicity and breadth of induced responses. Recent studies have elucidated the functional, dynamic and immunological features of key regions of the viral envelope glycoproteins, which can inform next-generation immunogen design efforts. These insights and design strategies represent promising pathways to HCV vaccine development, which can be further informed by successful immunogen designs generated for other viruses.
... Developing effective vaccination strategies for HCV presents a unique challenge, due to its antigenic heterogeneity and immune evasion mechanisms. Other antigenically diverse chronic viruses such as HIV-1 have explored the use of mosaic vaccines [161,162], polyvalent antigens [163,164], or heterologous prime boost strategies [165] to broaden both T and B cell immunity and serve as useful examples on which to base future strategies for HCV vaccine development. Considerable knowledge has now been gained to define key sites of vulnerability for antibody mediated neutralization on the E1E2 glycoprotein complex. ...
Article
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Direct-acting antiviral agents have proven highly effective at treating existing hepatitis C infections but despite their availability most countries will not reach the World Health Organization targets for elimination of HCV by 2030. A prophylactic vaccine remains a high priority. Whilst early vaccines focused largely on generating T cell immunity, attention is now aimed at vaccines that generate humoral immunity, either alone or in combination with T cell-based vaccines. High-resolution structures of hepatitis C viral glycoproteins and their interaction with monoclonal antibodies isolated from both cleared and chronically infected people, together with advances in vaccine technologies, provide new avenues for vaccine development.
... The clustered high-mannose patch as an antigenic epitope Even after 40 years of attempts, an effective vaccine against the HIV is still not available [145]. A late-stage clinical trial (NCT02315703) is going to start with the "mosaic" HIV-1 vaccine candidate [146] based on priming with adenovirus serotype 26 (Ad26) vectors, which encode for the Env/Gag/Pol antigens, and boosting with Ad26 in the presence of aluminumadjuvanted clade C Env gp140 protein. From a carbohydrate point of view, it is widely accepted that glycans play a key role in the immunology and pathology of HIV. ...
Article
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Vaccination is one of the greatest achievements in biomedical research preventing death and morbidity in many infectious diseases through the induction of pathogen‐specific humoral and cellular immune responses. Currently, no effective vaccines are available for pathogens with a highly variable antigenic load, such as the Human Immunodeficiency Virus or to induce cellular T cell immunity in the fight against cancer. The recent SARS‐CoV‐2 outbreak has reinforced the relevance of designing smart therapeutic vaccine modalities to ensure public health. Indeed, academic and private companies have ongoing joint efforts to develop novel vaccine prototypes for this virus. Many pathogens are covered by a dense glycan‐coat, which form an attractive target for vaccine development. Moreover, many tumor types are characterized by altered glycosylation profiles that are known as ‘tumor‐associated carbohydrate antigens’ (TACA). Unfortunately, glycans do not provoke a vigorous immune response and generally serve as T cell‐independent antigens, not eliciting protective IgG responses nor inducing immunological memory. A close and continuous crosstalk between glycochemists and glycoimmunologists is essential for the successful development of efficient immune modulators. It is clear that this is a key point for the discovery of novel approaches, which could significantly improve our understanding of the immune system. In this review, we discuss the latest advancements in development of vaccines against glycan epitopes to gain selective immune responses, and to provide an overview on the role of different immunogenic constructs in improving glycovaccine efficacy.
... We can hypothesize that pre-existing anti-Ad26 antibodies are more frequent in older adults than young adults and that their presence modifies the frequency of SAEs related to coagulative disorder and arterial, cardiac, and nervous system events. However, Dan Barouch and colleagues studying the effect of an adenovirus-based HIV vaccine suggest they do not [52]. Further studies are needed to understand the different frequencies of SAEs in young adults and older adult recipients of virus-based vaccines. ...
Article
The ChAdOx1 nCoV-19 (ChA) (AstraZeneca) and Ad26.COV2.S (AD26) (Janssen) vaccines are virus-based coronavirus disease 2019 (COVID-19) vaccines used worldwide. In spring 2021, venous blood clots and thrombocytopenia were described in some vaccine recipients. We evaluated the frequency of severe adverse events (SAEs) documented in the EudraVigilance European database in young adult (18–64 years old) and older (≥65 years old) vaccine recipients up to 23 June 2021 and related them to coagulation disorders and arterial, cardiac, and nervous system events. Comparison between the frequency of SAEs and SAE-related deaths in ChA and AD26 vs. BNT162b2 COVID-19 (BNT) (Pfizer/BioNTech) vaccine recipients demonstrated: 1) ChA and AD26 recipients than BNT recipients had higher frequencies of not only SAEs caused by venous blood clots and hemorrhage, but also thromboembolic disease and arterial events, including myocardial infarction and stroke; 2) a corresponding higher frequency of SAE-related deaths. The frequency was higher in both young adults and older adults. Comparison between the frequency of SAEs and SAE-related deaths in AD26 vs. ChA recipients demonstrated in AD26 recipients: 1) lower frequency of thrombocytopenia; 2) lower frequency of SAEs in young adult recipients; 3) higher frequency of SAEs in older recipients. Interestingly, most of the venous thrombotic SAEs associated with ChA and AD26 vaccines were not associated with thrombocytopenia, suggesting that TTS (thrombosis with thrombocytopenia syndrome) is not the only type of thrombosis observed following virus-based vaccines. In conclusion, both virus-based COVID-19 vaccines show more SAEs than BNT, but the frequency of the SAE type in the different age groups differs, suggesting that the mechanisms responsible of SAEs overlap only partly.
... (B) Immune response to the SARS-CoV-2 vaccine: Once in the human body, the different vaccine platforms will synthesize or deliver SARS-CoV-2 total or subunit spike protein which will induce specific memory immune response against SARS-CoV (rAd26-S and rAd5-S) [76]. Recombinant adenoviruses have been widely used for vaccine development such as hepatitis B, Ebola virus, RSV, HIV and Zika vaccines with an excellent safety profile confirmed in many clinical studies [77][78][79][80]. Moreover, recombinant adenovirus vectors elicit robust long-lasting immune response without the need of adjuvant after one or two doses of vaccine [81,82]. ...
Article
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The emergence of novel and evolving variants of SARS-CoV-2 has fostered the need for change in the form of newer and more adaptive diagnostic methods for the detection of SARS-CoV-2 infections. On the other hand, developing rapid and sensitive diagnostic technologies is now more challenging due to emerging variants and varying symptoms exhibited among the infected individuals. In addition to this, vaccines remain the major mainstay of prevention and protection against infection. Novel vaccines and drugs are constantly being developed to unleash an immune response for the robust targeting of SARS-CoV-2 and its associated variants. In this review, we provide an updated perspective on the current challenges posed by the emergence of novel SARS-CoV-2 mutants/variants and the evolution of diagnostic techniques to enable their detection. In addition, we also discuss the development, formulation, working mechanisms, advantages, and drawbacks of some of the most used vaccines/therapeutic drugs and their subsequent immunological impact.Key messageThe emergence of novel variants of the SARS-CoV-2 in the past couple of months, highlights one of the primary challenges in the diagnostics, treatment, as well as vaccine development against the virus.Advancements in SARS-CoV-2 detection include nucleic acid based, antigen and immuno- assay-based and antibody-based detection methodologies for efficient, robust, and quick testing; while advancements in COVID-19 preventive and therapeutic strategies include novel antiviral and immunomodulatory drugs and SARS-CoV-2 targeted vaccines.The varied COVID-19 vaccine platforms and the immune responses induced by each one of them as well as their ability to battle post-vaccination infections have all been discussed in this review. Keywords: COVID-19; Coronaviruses; Omicron; SARS-CoV-2; Viral epidemic; diagnostic testing; immunological responses; vaccine.
... were linked to protective immunity in an NHP challenge study. 76,77 Likewise, antibody Fc effector functions were observed following SARS-CoV-2 Ad26 vaccination in humans, 78 NHP, 79 of concern whereas antibodies induced via natural infection, 84,85 adjuvanted-protein immunization, 86 or adenoviral vaccination did not, 87 marking potentially distinct cross-reactive Fc-effector induction across vaccine platforms. Thus, while Fc-effector function co-evolves with binding titers across all vaccine platforms tested to date, the flexibility of the cross-variant Fc-effector response may vary across vaccine platform. ...
Article
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Antibodies against epitopes in S1 give the most accurate CoP against infection by the SARS‐CoV‐2 coronavirus. Measurement of those antibodies by neutralization or binding assays both have predictive value, with binding antibody titers giving the highest statistical correlation. However, the protective functions of antibodies are multiple. Antibodies with multiple functions other than neutralization influence efficacy. The role of cellular responses can be discerned with respect to CD4⁺ T cells and their augmentation of antibodies, and with respect to CD8⁺ cells with regard to control of viral replication, particularly in the presence of insufficient antibody. More information is needed on mucosal responses.
... Thus, there is a suggested risk of ADE in SARS-CoV-2 vaccines and antibody-based interventions that should receive attention [36]. Recombinant replication-incompetent adenoviruses have an acceptable safety profile in humans and are able to induce neutralizing antibodies, CD4 and CD8 T cell responses and a Th1-biased immune response in animals and humans [42][43][44][45]. Recently, a study showed that 9. Induction of pre-existing anti-Ad antibody following immunization of AdCoV2 vaccine in hamster. ...
Article
A series of recombinant human type 5 adenoviruses that express the full-length or membrane-truncated spike protein (S) of SARS-CoV-2 (AdCoV2-S or AdCoV2-SdTM, respectively) was tested the efficacy against SARS-CoV-2 via intranasal (i.n.) or subcutaneous (s.c.) immunization in a rodent model. Mucosal delivery of adenovirus (Ad) vaccines could induce anti-SARS-CoV-2 IgG and IgA in the serum and in the mucosal, respectively as indicated by vaginal wash (vw) and bronchoalveolar lavage fluid (BALF). Serum anti-SARS-CoV-2 IgG but not IgA in the vw and BALF was induced by AdCoV2-S s.c.. Administration of AdCoV2-S i.n. was able to induce higher anti-SARS-CoV-2 binding and neutralizing antibody levels than s.c. injection. AdCoV2-SdTM i.n. induced a lower antibody responses than AdCoV2-S i.n.. Induced anti-S antibody responses by AdCoV2-S via i.n. or s.c. were not influenced by the pre-existing serum anti-Ad antibody. Novelty, S-specific IgG1 which represented Th2-mediated humoral response was dominantly induced in Ad i.n.-immunized serum in contrast to more IgG2a which represented Th1-mediated cellular response found in Ad s.c.-immunized serum. The activation of S-specific IFN-ɣ and IL-4 in splenic Th1 and Th2 cells, respectively, was observed in the AdCoV2-S i.n. and s.c. groups, indicating the Th1 and Th2 immunity were activated. AdCoV2-S and AdCoV2-SdTM significantly prevented body weight loss and reduced pulmonary viral loads in hamsters. A reduction in inflammation in the lungs was observed in AdCoV-S via i.n. or s.c.-immunized hamsters following a SARS-CoV-2 challenge. It correlated to Th1 cytokine but no inflammatory cytokines secretions found in AdCoV-S i.n. -immunized BALF. These results indicate that intranasal delivery of AdCoV2-S vaccines is safe and potent at preventing SARS-CoV-2 infections.
... A recent randomized placebo-controlled double-blinded Phase I Ad26/MVA therapeutic vaccine trial (RV405) reported a modest delay in viral rebound, suggesting that current therapeutic vaccine strategies induce inadequate cellular immune breadth in humans 25 . Additional studies have shown that Ad26 or MVA vaccination in combination with an SIV Env subunit boost induced robust cellular immune responses in uninfected rhesus macaques, proving a means to improve overall cellular immune breadth 26,27 . Furthermore, a recent trial consisting of HIV-1 controllers given a total of ten doses of vesatolimod while virologically suppressed demonstrated a modest delay in viral rebound following ART interruption of approximately one week with four individuals from the treatment group showing a delay in rebound of more than 6 weeks 22 . ...
Article
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Developing an intervention that results in virologic control following discontinuation of antiretroviral therapy (ART) is a major objective of HIV-1 cure research. In this study, we investigated the therapeutic efficacy of a vaccine consisting of adenovirus serotype 26 (Ad26) and modified vaccinia Ankara (MVA) with or without an SIV Envelope (Env) gp140 protein with alum adjuvant in combination with the TLR7 agonist vesatolimod (GS-9620) in 36 ART-suppressed, SIVmac251-infected rhesus macaques. Ad26/MVA therapeutic vaccination led to robust humoral and cellular immune responses, and the Env protein boost increased antibody responses. Following discontinuation of ART, virologic control was observed in 5/12 animals in each vaccine group, compared with 0/12 animals in the sham control group. These data demonstrate therapeutic efficacy of Ad26/MVA vaccination with vesatolimod but no clear additional benefit of adding an Env protein boost. SIV-specific cellular immune responses correlated with virologic control. Our findings show partial efficacy of therapeutic vaccination following ART discontinuation in SIV-infected rhesus macaques.
... Identifier: NCT04066881) following proof-of-concept in macaque studies [13][14][15]. Despite mosaic antigen vaccines showing promising results in macaques [16], the HVTN 705/HPX2008/Imbokodo study (ClinicalTrials.gov Identifier: NCT03060629) testing a mosaic-based vaccine in young women at high risk of acquiring HIV was also discontinued due to futility, as announced by the International AIDS Vaccine Initiative (https://www.iavi.org/news-resources/features/iavi-statement-on-resultsfrom-phase-iib-imbokodo-hiv-vaccine-clinical-trial) ...
Article
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Non-human primates (NHPs) remain the most relevant challenge model for the evaluation of HIV vaccine candidates; however, discrepancies with clinical trial results have emphasized the need to further refine the NHP model. Furthermore, classical evaluation of vaccine candidates is based on endpoints measured systemically. We assessed the mucosal responses elicited upon vaccination with ALVAC and AIDSVAX using ex vivo Rhesus macaque mucosal tissue explant models. Following booster immunization with ALVAC/AIDSVAX, anti-gp120 HIV-1CM244-specific IgG and IgA were detected in culture supernatant cervicovaginal and colorectal tissue explants, as well as systemically. Despite protection from ex vivo viral challenge, no neutralization was observed with tissue explant culture supernatants. Priming with ALVAC induced distinct cytokine profiles in cervical and rectal tissue. However, ALVAC/AIDSVAX boosts resulted in similar modulations in both mucosal tissues with a statistically significant decrease in cytokines linked to inflammatory responses and lymphocyte differentiation. With ALVAC/AIDSVAX boosts, significant correlations were observed between cytokine levels and specific IgA in cervical explants and specific IgG and IgA in rectal tissue. The cytokine secretome revealed differences between vaccination with ALVAC and ALVAC/AIDSVAX not previously observed in mucosal tissues and distinct from the systemic response, which could represent a biosignature of the vaccine combination.
... In the context of HIV vaccine research, however, adenoviruses were identified early on as a promising platform to recruit both humoral and cellular arms of the immune response. Two types of adenoviruses, in particular, have been the focus of HIV vaccine platforms: an adenovirus that infects chimpanzees [3,4] and a specific but rare serotype that infects humans [5]. Both viruses have since been used as viral vectors for two SARS-CoV-2 vaccines that are currently in use worldwide (ChAdOx-1 nCoV-19 and Ad26.COV2.S) [6,7]. ...
Article
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Purpose of Review This review examines the major advances and obstacles in the field of HIV vaccine research as they pertain to informing the development of vaccines against SARS-CoV-2. Recent Findings Although the field of HIV research has yet to deliver a licensed vaccine, the technologies developed and knowledge gained in basic scientific disciplines, translational research, and community engagement have positively impacted the development of vaccines for other viruses, most notably and recently for SARS-CoV-2. These advances include the advent of viral vectors and mRNA as vaccine delivery platforms; the use of structural biology for immunogen design; an emergence of novel adjuvant formulations; a more sophisticated understanding of viral phylogenetics; improvements in the development and harmonization of accurate assays for vaccine immunogenicity; and maturation of the fields of bioethics and community engagement for clinical trials conducted in diverse populations. Summary Decades of foundational research and investments into HIV biology, though yet to yield an authorized or approved vaccine for HIV/AIDS, have now paid dividends in the rapid development of safe and effective SARS-CoV-2 vaccines. This latter success presents an opportunity for feedback on improved pathways for development of safe and efficacious vaccines against HIV and other pathogens.
... In collaboration with the healthcare company Johnson and Johnson (J & J), researchers at Beth Israel Deaconess Medical Center developed a replication-defective adenovirus serotype 26 (Ad26)-based COVID-19 vaccine (Ad26.COV2.S, immunogen: S.PP), and investigated its immunogenicity in animal models [10,11]. In line with other Ad26-vectored vaccines [12][13][14][15], Ad26.COV2.S induced strong humoral and cellular immune responses. In golden Syrian hamsters, a single immunization of high dose (10 10 viral particles (vp)) or low dose (10 9 vp) of Ad26.COV2.S via the intramuscular route (IM) led to strong receptor binding domain (RBD)-specific binding antibody and neutralizing antibody (NAb) responses, and protected against SARS-CoV-2-induced weight loss, pneumonia, and mortality [10]. ...
Article
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The persistent expansion of the coronavirus disease 2019 (COVID-19) global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires the rapid development of safe and effective countermeasures to reduce transmission, morbidity, and mortality. Several highly efficacious vaccines are actively being deployed around the globe to expedite mass vaccination and control of COVID-19. Notably, viral vectored vaccines (VVVs) are among the first to be approved for global distribution and use. In this review, we examine the humoral, cellular, and innate immune responses elicited by viral vectors, and the immune correlates of protection against COVID-19 in preclinical and clinical studies. We also discuss the durability and breadth of immune response induced by VVVs and boosters. Finally, we present challenges associated with VVVs and offer solutions for overcoming certain limitations of current vaccine regimens. Collectively, this review provides the rationale for expanding the portfolio of VVVs against SARS-CoV-2.
Article
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Despite the advent of long-acting anti-retroviral therapy able to control and prevent infection, a preventative vaccine remains a global priority for the elimination of HIV. The moderately protective RV144 vaccine trial suggested functional IgG1 and IgG3 antibodies were a potential correlate of protection, but the RV144-inspired HVTN702 validation trial failed to demonstrate efficacy despite inducing targeted levels of IgG1/IgG3. Alterations in inserts, and antigens, adjuvant, and regimen also resulted in vaccine induced target quantitative levels of the immune correlates, but drove qualitative changes to the humoral immune response, pointing to the urgent need to define the influence of vaccine strategies on shaping antibody quality, not just quantity. Thus, defining how distinct prime/boost approaches tune long-lived functional antibodies represents an important goal in vaccine development. Here, we compared vaccine responses in Phase I and II studies in humans utilizing various combinations of DNA/vector, vector/vector and DNA/protein HIV vaccines. We found that adenoviral vector immunization, compared to pox-viral vectors, resulted in the most potent IgG1 and IgG3 responses, linked to highly functional antibody activity, including assisting NK cell related functions. Minimal differences were observed in the durability of the functional humoral immune response across vaccine regimens, except for antibody dependent phagocytic function, which persisted for longer periods in the DNA/rAd5 and rAd35/rAd5 regimen, likely driven by higher IgG1 levels. Collectively, these findings suggest adenoviral vectors drive superior antibody quality and durability that could inform future clinical vaccine studies. Trial registration : ClinicalTrials.gov NCT00801697 , NCT00961883 , NCT02207920 , NCT00125970 , NCT02852005 ).
Article
Background While social distancing is a key public health response during viral pandemics, psychosocial stressors, such as social isolation, have been implicated in adverse health outcomes in general (1) and in the context of infectious disease, such as HIV (2,3). A comprehensive understanding of the direct pathophysiologic effects of psychosocial stress on viral pathogenesis is needed to provide strategic and comprehensive care to patients with viral infection. Methods To determine the effect of psychosocial stress on HIV pathogenesis during acute viral infection without sociobehavioral confounders inherent in human cohorts, we compared commonly measured parameters of HIV progression between singly (n=35) and socially (n=41) housed SIV-infected pigtailed macaques (Macaca nemestrina). Results Singly housed macaques had a higher viral load in the plasma and cerebrospinal fluid and demonstrated greater CD4 T cell declines and more CD4 and CD8 T cell activation compared to socially housed macaques throughout acute SIV infection. Conclusions These data demonstrate that psychosocial stress directly impacts the pathogenesis of acute SIV infection and imply that it may act as an integral variable in the progression of HIV infection and potentially of other viral infections.
Article
In the evolutionary battle between virus and host, a genetic alteration in cytomegalovirus caused by an inversion-deletion event during tissue culture passage opens an unconventional path toward an HIV vaccine (see the related Research Articles by Malouli et al. , Yang et al. , and Verweij et al. ).
Article
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Eliciting broadly neutralizing antibodies (bnAbs) is a cornerstone of HIV-1 vaccine strategies. Comparing HIV-1 envelope (env) sequences from the first weeks of infection to the breadth of antibody responses observed several years after infection can help define viral features critical to vaccine design. We investigated the relationship between HIV-1 env genetics and the development of neutralization breadth in 70 individuals enrolled in a prospective acute HIV-1 cohort. Half of the individuals who developed bnAbs were infected with multiple HIV-1 founder variants, whereas all individuals with limited neutralization breadth had been infected with single HIV-1 founders. Accordingly, at HIV-1 diagnosis, env diversity was significantly higher in participants who later developed bnAbs compared to those with limited breadth (p = 0.012). This association between founder multiplicity and the subsequent development of neutralization breadth was also observed in 56 placebo recipients in the RV144 vaccine efficacy trial. In addition, we found no evidence that neutralization breath was heritable when analyzing env sequences from the 126 participants. These results demonstrate that the presence of slightly different HIV-1 variants in acute infection could promote the induction of bnAbs, suggesting a novel vaccine strategy, whereby an initial immunization with a cocktail of minimally distant antigens would be able to initiate bnAb development towards breadth.
Article
Due to their nature, adenoviruses have been recognised as promising candidates for vaccine vector development. Since they mimic natural infection, recombinant adenovirus vectors have been proven as ideal shuttles to deliver foreign transgenes aiming at inducing both humoral and cellular immune response. In addition, a potent adjuvant effect can be exerted due to the adenovirus inherent stimulation of various elements of innate and adaptive immunity. Due to its low seroprevalence in humans as well as induction of favourable immune response to inserted transgene, human adenovirus type 26 (HAdV‐D26) has been recognised as a promising platform for vaccine vector development and is studied in number of completed or ongoing clinical studies. Very recently HAdV‐D26 based Ebola and Covid‐19 vaccines were approved for medical use. In this review, current state of the art regarding HAdV‐D26 basic biology and its usage as vaccine vector will be discussed.
Article
This review discusses peptide epitopes used as antigens in the development of vaccines in clinical trials as well as future vaccine candidates. It covers peptides used in potential immunotherapies for infectious diseases including SARS-CoV-2, influenza, hepatitis B and C, HIV, malaria, and others. In addition, peptides for cancer vaccines that target examples of overexpressed proteins are summarized, including human epidermal growth factor receptor 2 (HER-2), mucin 1 (MUC1), folate receptor, and others. The uses of peptides to target cancers caused by infective agents, for example, cervical cancer caused by human papilloma virus (HPV), are also discussed. This review also provides an overview of model peptide epitopes used to stimulate non-specific immune responses, and of self-adjuvanting peptides, as well as the influence of other adjuvants on peptide formulations. As highlighted in this review, several peptide immunotherapies are in advanced clinical trials as vaccines, and there is great potential for future therapies due the specificity of the response that can be achieved using peptide epitopes.
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Background: VRC01, a potent, broadly-neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. HVTN 104 assessed VRC01 safety and pharmacokinetics in humans. We extend the clinical evaluation to determine intravenous-infused VRC01 distribution and protective function at mucosal sites of HIV-1 entry. Methods: Healthy, HIV-1-uninfected men (n=7) and women (n=5) receiving VRC01 every two months provided mucosal and serum samples once, 4-13 days post-infusion. Eleven male and 8 female HIV-seronegative volunteers provided untreated control samples. VRC01 levels were measured in serum, secretions and tissue, and HIV-1 inhibition was determined in tissue explants. Results: Median VRC01 levels were quantifiable in serum (96.2 µg/ml or 1.3 pg/ng protein), rectal tissue (0.11 pg/ng protein), rectal secretions (0.13 pg/ng protein), vaginal tissue (0.1 pg/ng protein) and cervical secretions (0.44 pg/ng protein) from all recipients. VRC01/IgG ratios in male serum correlated with those in paired rectal tissue (r=0.893, P=0.012) and rectal secretions (r=0.9643, P=0.003). Ex vivo HIV-1Bal26 challenge infected 4/21 rectal explants from VRC01-infused versus 20/22 from controls (P=0.005); HIV-1 Du422.1 infected 20/21 rectal explants of VRC01 recipients and 12/12 from controls (P=0.639). HIV-1Bal26 infected 0/14 vaginal explants of VRC01 recipients compared to 23/28 control explants (P=0.003). Conclusion: Intravenous VRC01 distributes into the female genital and male rectal mucosa and retains anti-HIV-1 functionality, inhibiting a highly neutralization-sensitive but not a highly-resistant HIV-1 strain in mucosal tissue. These findings lend insight into VRC01 mucosal infiltration and provide perspective to in vivo protective efficacy. Funding: National Institute of Allergy and Infectious Diseases and Bill & Melinda Gates Foundation.
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Modern vaccinology has experienced major conceptual and technological advances over the past 30 years. These include atomic-level structures driving immunogen design, new vaccine delivery methods, powerful adjuvants, and novel animal models. In addition, utilizing advanced assays to learn how the immune system senses a pathogen and orchestrates protective immunity has been critical in the design of effective vaccines and therapeutics. The National Institute of Allergy and Infectious Diseases of the National Institutes of Health convened a workshop in September 2020 focused on next generation assays for vaccine development (Table 1). The workshop focused on four critical pathogens: severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and human immunodeficiency virus (HIV)—which have no licensed vaccines—and tuberculosis (TB) and influenza—both of which are in critical need of improved vaccines. The goal was to share progress and lessons learned, and to identify any commonalities that can be leveraged to design vaccines and therapeutics.
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HIV is a virus that remains a major health concern and results in an infection that has no cure even after over 30 years since its discovery. As such, HIV vaccine discovery continues to be an area of intensive research. In this review, we summarize the most recent HIV vaccine efficacy trials, clinical trials initiated within the last 3 years, and discuss prominent improvements that have been made in prophylactic HIV vaccine designs.
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The development of a protective vaccine remains a top priority for the control of the HIV/AIDS pandemic. Here, we show that a messenger RNA (mRNA) vaccine co-expressing membrane-anchored HIV-1 envelope (Env) and simian immunodeficiency virus (SIV) Gag proteins to generate virus-like particles (VLPs) induces antibodies capable of broad neutralization and reduces the risk of infection in rhesus macaques. In mice, immunization with co-formulated env and gag mRNAs was superior to env mRNA alone in inducing neutralizing antibodies. Macaques were primed with a transmitted-founder clade-B env mRNA lacking the N276 glycan, followed by multiple booster immunizations with glycan-repaired autologous and subsequently bivalent heterologous envs (clades A and C). This regimen was highly immunogenic and elicited neutralizing antibodies against the most prevalent (tier-2) HIV-1 strains accompanied by robust anti-Env CD4+ T cell responses. Vaccinated animals had a 79% per-exposure risk reduction upon repeated low-dose mucosal challenges with heterologous tier-2 simian–human immunodeficiency virus (SHIV AD8). Thus, the multiclade env–gag VLP mRNA platform represents a promising approach for the development of an HIV-1 vaccine. An mRNA vaccine platform to prevent HIV-1 infection generated broadly neutralizing antibodies in non-human primates and protected some animals from infection, raising hope that optimization of this approach might lead to an effective HIV vaccine.
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Zoonotic viruses continually pose a pandemic threat. Infection of humans with viruses for which we typically have little or no prior immunity, can result in epidemics with high morbidity and mortality. These epidemics can have public health and economic impact, and can exacerbate civil unrest or political instability. Changes in human behavior in the past few decades: increased global travel, farming intensification, the exotic animal trade, as well as the impact of global warming on animal migratory patterns, habitats and ecosystems, contribute to the increased frequency of cross-species transmission events. Investing in the pre-clinical advancement of vaccine candidates against diverse emerging viral threats is crucial for pandemic preparedness. Replication-defective adenoviral (Ad) vectors have demonstrated their utility as an outbreak-responsive vaccine platform during the SARS-CoV-2 pandemic. Ad vectors are easy to engineer, are amenable to rapid, inexpensive manufacturing, are relatively safe and immunogenic in humans, and importantly, and do not require specialized cold-chain storage, making them an ideal platform for equitable global distribution, or stockpiling. In this review, we discuss the progress in applying Ad-based vaccines against emerging viruses, and summarize their global safety profile, as reflected by their widespread geographic use during the SARS-CoV-2 pandemic.
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Although the BCG vaccine offers partial protection, tuberculosis remains a leading cause of infectious disease death, killing ∼1.5 million people annually. We developed mucosal vaccines expressing the autophagy-inducing peptide C5 and mycobacterial Ag85B-p25 epitope using replication-defective human adenovirus (HAdv85C5) and bovine adenovirus (BAdv85C5) vectors. BAdv85C5-infected dendritic cells (DCs) expressed a robust transcriptome of genes regulating antigen processing compared to HAdv85C5-infected DCs. BAdv85C5-infected DCs showed enhanced galectin-3/8 and autophagy-dependent in vitro Ag85B-p25 epitope presentation to CD4 T cells. BCG-vaccinated mice were intranasally boosted using HAdv85C5 or BAdv85C5 followed by infection using aerosolized Mycobacterium tuberculosis (Mtb). BAdv85C5 protected mice against tuberculosis both as a booster after BCG vaccine (>1.4-log10 reduction in Mtb lung burden) and as a single intranasal dose (>0.5-log10 reduction). Protection was associated with robust CD4 and CD8 effector (TEM), central memory (TCM), and CD103⁺/CD69⁺ lung-resident memory (TRM) T cell expansion, revealing BAdv85C5 as a promising mucosal vaccine for tuberculosis.
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Almost four decades on, since the 1980’s, with hundreds of HIV vaccine candidates tested in both non-human primates and humans, and several HIV vaccines trials later, an efficacious HIV vaccine continues to evade us. The enormous worldwide genetic diversity of HIV, combined with HIV’s inherent recombination and high mutation rates, has hampered the development of an effective vaccine. Despite the advent of antiretrovirals as pre-exposure prophylaxis and preventative treatment, which have shown to be effective, HIV infections continue to proliferate, highlighting the great need for a vaccine. Here, we provide a brief history for the HIV vaccine field, with the most recent disappointments and advancements. We also provide an update on current passive immunity trials, testing proof of the concept of the most clinically advanced broadly neutralizing monoclonal antibodies for HIV prevention. Finally, we include mucosal immunity, the importance of vaccine-elicited immune responses and the challenges thereof in the most vulnerable environment–the female genital tract and the rectal surfaces of the gastrointestinal tract for heterosexual and men who have sex with men transmissions, respectively.
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Viral vector vaccines use harmless, non-replicating or replicating viruses to deliver genetic material for production of vaccine antigens into host cell cytoplasm. While viral vector vaccines may theoretically induce life-long immunity with low antigen concentrations, their attenuation, safety and spread to the community are of concern. Vaccines based on recombinant viral vectors can induce both humoral and cellular immune responses. Adenovirus vectors are versatile gene transfer vectors that can be easily manufactured, and which may allow simultaneous expression of multiple antigens by a single vector construct. Adenovirus vector vaccines based on the adenovirus Ad26 vector have been widely used as vaccines against Ebola and COVID19 (see Chapters 44 and 56). A common concern of using viral vector vaccines is pre-existing immunity or induction of immunity against the vector itself, but in some circumstances it has no meaningful impact and it can be resolved in several ways. Several harmless viruses are already used as vectors for innovative vaccines and many more are in research.
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A gene signature previously correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus (SIV) and SHIV challenge models in non-human primates (NHP). In this report we investigated presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanisms of protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial, which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy. Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage, including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with vaccine efficacy represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate development of new vaccine candidates.
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Conventional influenza vaccines fail to confer broad protection against diverse influenza A viruses with pandemic potential. Efforts to develop a universal influenza virus vaccine include refocusing immunity towards the highly conserved stalk domain of the influenza virus surface glycoprotein, hemagglutinin (HA). We constructed a non-replicating adenoviral (Ad) vector, encoding a secreted form of H1 HA, to evaluate HA stalk-focused immunity. The Ad5_H1 vaccine was tested in mice for its ability to elicit broad, cross-reactive protection against homologous, heterologous and heterosubtypic lethal challenge, in a single-shot immunization regimen. Ad5_H1 elicited hemagglutination inhibition (HI⁺) active antibodies (Abs), which conferred 100% sterilizing protection from homologous H1N1 challenge. Furthermore, Ad5_H1 rapidly induced H1 stalk-specific Abs with Fc-mediated effector function activity, in addition to stimulating both CD4⁺ and CD8⁺ stalk-specific T cell responses. This phenotype of immunity provided 100% protection from lethal challenge with a head-mismatched, reassortant influenza virus bearing a chimeric HA, cH6/1, in a stalk-mediated manner. Most importantly, 100% protection from mortality following lethal challenge with a heterosubtypic avian influenza virus, H5N1, was observed following a single immunization with Ad5_H1. In conclusion, Ad-based influenza vaccines can elicit significant breadth of protection in naïve animals and could be considered for pandemic preparedness and stockpiling.
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COVID-19, the disease caused by the SARS-CoV-2 betacoronavirus, was declared a pandemic by the World Health Organization on March 11, 2020. Since then, SARS-CoV-2 has triggered a devastating global health and economic emergency.In response, a broad range of preclinical animal models have been used to identify effective therapies and vaccines. Current animal models do not express the full spectrum of human COVID-19 disease and pathology, with most exhibiting mild to moderate disease without mortality. NHPs are physiologically, genetically, and immunologically more closely related to humans than other animal species; thus, they provide a relevant model for SARS-CoV-2 investigations. This overview summarizes NHP models of SARS-CoV-2 and their role in vaccine and therapeutic development.
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Since its emergence in late 2019, the coronavirus disease 2019 (COVID‐19) pandemic has caused substantial morbidity and mortality. Despite the availability of efficacious vaccines, new variants with reduced sensitivity to vaccine‐induced protection are a troubling new reality. The Ad26.COV2.S vaccine is a recombinant, replication‐incompetent human adenovirus type 26 vector encoding a full‐length, membrane‐bound severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike protein in a prefusion‐stabilized conformation. This review discusses the immunogenicity and efficacy of Ad26.COV2.S as a single‐dose primary vaccination and as a homologous or heterologous booster vaccination. Ad26.COV2.S elicits broad humoral and cellular immune responses, which are associated with protective efficacy/effectiveness against SARS‐CoV‐2 infection, moderate to severe/critical COVID‐19, and COVID‐19–related hospitalization and death, including against emerging SARS‐CoV‐2 variants. The humoral immune responses elicited by Ad26.COV2.S vaccination are durable, continue to increase for at least 2‐3 months postvaccination, and involve a range of functional antibodies. Ad26.COV2.S given as a heterologous booster to mRNA vaccine–primed individuals markedly increases humoral and cellular immune responses. The use of Ad26.COV2.S as primary vaccination and as part of booster regimens is supporting the ongoing efforts to control and mitigate the COVID‐19 pandemic.
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Objectives To assess the benefits and harms of aluminium adjuvants versus placebo or no intervention in randomised clinical trials in relation to human vaccine development. Design Systematic review with meta-analysis and trial sequential analysis assessing the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). Data sources We searched CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, Science Citation Index Expanded and Conference Proceedings Citation Index-Science until 29 June 2021, and Chinese databases until September 2021. Eligibility criteria Randomised clinical trials irrespective of type, status and language of publication, with trial participants of any sex, age, ethnicity, diagnosis, comorbidity and country of residence. Data extraction and synthesis Two independent reviewers extracted data and assessed risk of bias with Cochrane’s RoB tool 1. Dichotomous data were analysed as risk ratios (RRs) and continuous data as mean differences. We explored both fixed-effect and random-effects models, with 95% CI. Heterogeneity was quantified with I ² statistic. We GRADE assessed the certainty of the evidence. Results We included 102 randomised clinical trials (26 457 participants). Aluminium adjuvants versus placebo or no intervention may have no effect on serious adverse events (RR 1.18, 95% CI 0.97 to 1.43; very low certainty) and on all-cause mortality (RR 1.02, 95% CI 0.74 to 1.41; very low certainty). No trial reported on quality of life. Aluminium adjuvants versus placebo or no intervention may increase adverse events (RR 1.13, 95% CI 1.07 to 1.20; very low certainty). We found no or little evidence of a difference between aluminium adjuvants versus placebo or no intervention when assessing serology with geometric mean titres or concentrations or participants’ seroprotection. Conclusions Based on evidence at very low certainty, we were unable to identify benefits of aluminium adjuvants, which may be associated with adverse events considered non-serious.
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BACKGROUND To assess the impact of combination HIV prevention (CHP) on HIV incidence, we analyzed the association between HIV incidence and scale-up of antiretroviral therapy (ART) and medical male circumcision in Rakai, Uganda. Changes in population-level viral load suppression and sexual behaviors were also examined. METHODS Between 1999 and 2016, data were collected through 12 surveys from 30 communities in the Rakai Community Cohort Study, an open population-based cohort of persons aged 15-49 years. We assessed HIV incidence trends based on observed seroconversion data, self-reported ART and male circumcision coverage, viral load suppression, and sexual behaviors. RESULTS In total, 33,937 study participants contributed 103,011 person-visits (HIV prevalence ~13%). Follow-up of 17,870 HIV-negative persons contributed 94,427 person-years with 931 seroconversions. ART was introduced in 2004; by 2016 coverage was 69% (72% in women vs. 61% in men, p<0.001). HIV viral load suppression among all HIV-positive persons increased from 42% in 2009 to 75% by 2016 (p<0.001). Male circumcision coverage increased from 15% in 1999 to 59% by 2016 (p<0.001). Persons 15-19 years reporting n 71 ever having sex increased from 30% to 55% (p<0.0001). HIV incidence declined by 42% in 2016 relative to the pre-CHP period prior to 2010 (1.17/100 py to 0.66/100 py; adjIRR:0.58: 95%CI: 0.45-0.76); declines were greater in men (adjIRR=0.46; 95%CI: 0.29-0.73) than women (adjIRR=0.68, 95%CI: 0.50-0.94). CONCLUSIONS In this longitudinal study, HIV incidence significantly declined with CHP scale-up, providing empiric evidence that HIV control interventions can have substantial population-level impact. However, additional efforts are needed to overcome gender disparities and achieve HIV elimination.
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Importance: New data and therapeutic options warrant updated recommendations for the use of antiretroviral drugs (ARVs) to treat or to prevent HIV infection in adults. Objective: To provide updated recommendations for the use of antiretroviral therapy in adults (aged ≥18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis. Evidence review: A panel of experts in HIV research and patient care convened by the International Antiviral Society-USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted in the PubMed and EMBASE databases through April 2016. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence. Findings: Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count. Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs. Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided. Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities. Laboratory assessments are recommended before treatment, and monitoring during treatment is recommended to assess response, adverse effects, and adherence. Approaches are recommended to improve linkage to and retention in care are provided. Daily tenofovir disoproxil fumarate/emtricitabine is recommended for use as preexposure prophylaxis to prevent HIV infection in persons at high risk. When indicated, postexposure prophylaxis should be started as soon as possible after exposure. Conclusions and relevance: Antiretroviral agents remain the cornerstone of HIV treatment and prevention. All HIV-infected individuals with detectable plasma virus should receive treatment with recommended initial regimens consisting of an InSTI plus 2 NRTIs. Preexposure prophylaxis should be considered as part of an HIV prevention strategy for at-risk individuals. When used effectively, currently available ARVs can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults.
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The biggest roadblock in development of effective vaccines against human immunodeficiency virus type 1 (HIV-1) is the virus genetic diversity. For T-cell vaccine, this can be tackled by focusing the vaccine-elicited T cells on the highly functionally conserved regions of HIV-1 proteins, mutations in which typically cause a replicative fitness loss, and by computing multivalent mosaic proteins, which maximize the coverage of potential 9-mer T-cell epitopes of the input viral sequences. Our first conserved region vaccines HIVconsv employed clade alternating consensus sequences and showed promise in the initial clinical trials in terms of magnitude and breadth of elicited CD8(+) T cells. Here, monitoring T cells restricted by HLA-A*02:01 in transgenic mice, we assessed whether or not the tHIVconsv design (HIVconsv with a tissue plasminogen activator leader sequence) benefits from combining with a complementing conserved mosaic immunogen tHIVcmo, and compared the bivalent immunization to that with trivalent conserved mosaic vaccines. A hierarchy of tHIVconsv ≤ tHIVconsv+tHIVcmo < tCmo1+tCmo2+tCmo3 vaccinations for induction of CD8(+) T-cell responses was observed in terms of recognition of tested peptide variants. Thus, our HLA-A*02:01-restricted epitope data concur with previously published mouse and macaque observations and suggest that even conserved region vaccines benefit from oligovalent mosaic design.Molecular Therapy (2015); doi:10.1038/mt.2015.210.
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Preclinical studies of viral vector-based HIV-1 vaccine candidates have previously shown partial protection against neutralization-resistant virus challenges in rhesus monkeys. In this study, we evaluated the protective efficacy of adenovirus serotype 26 (Ad26) vector priming followed by purified envelope (Env) glycoprotein boosting. Rhesus monkeys primed with Ad26 vectors expressing SIVsmE543 Env, Gag, and Pol and boosted with AS01B-adjuvanted SIVmac32H Env gp140 demonstrated complete protection in 50% of vaccinated animals against a series of repeated, heterologous, intrarectal SIVmac251 challenges that infected all controls. Protective efficacy correlated with the functionality of Env-specific antibody responses. Comparable protection was also observed with a similar Ad/Env vaccine against repeated, heterologous, intrarectal SHIV-SF162P3 challenges. These data demonstrate robust protection by Ad/Env vaccines against acquisition of neutralization-resistant virus challenges in rhesus monkeys. Copyright © 2015, American Association for the Advancement of Science.
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Background: Defining mucosal immune responses and inflammation to candidate human immunodeficiency virus type 1 (HIV-1) vaccines represents a current research priority for the HIV-1 vaccine field. In particular, it is unclear whether intramuscular immunization can elicit immune responses at mucosal surfaces in humans. Methods: In this double-blind, randomized, placebo-controlled clinical trial, we evaluated systemic and mucosal immune responses to a candidate adenovirus serotype 26 (Ad26) vectored HIV-1 envelop (Env) vaccine in baseline Ad26-seronegative and Ad26-seropositive healthy volunteers. Systematic mucosal sampling with rectal Weck-Cel sponges and rectal biopsies were performed. Results: Intramuscular immunization elicited both systemic and mucosal Env-specific humoral and cellular immune responses in the majority of subjects. Individuals with preexisting Ad26-specific neutralizing antibodies had vaccine-elicited immune responses comparable to those of subjects who were Ad26 seronegative. We also observed no increase in activated total or vector-specific mucosal CD4+ T lymphocytes following vaccination by either histopathology or flow cytometry. Conclusions: These data demonstrate that a single intramuscular administration of this Ad26-vectored HIV-1 Env vaccine elicited both systemic and mucosal immune responses in humans. Induction of antigen-specific humoral and cellular mucosal immunity was not accompanied by a detectable increase in mucosal inflammation. Clinical trials registration: NCT01103687.
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BackgroundA safe and effective vaccine for the prevention of human immunodeficiency virus type 1 (HIV-1) infection is a global priority. We tested the efficacy of a DNA prime-recombinant adenovirus type 5 boost (DNA/rAd5) vaccine regimen in persons at increased risk for HIV-1 infection in the United States. Methods At 21 sites, we randomly assigned 2504 men or transgender women who have sex with men to receive the DNA/rAd5 vaccine (1253 participants) or placebo (1251 participants). We assessed HIV-1 acquisition from week 28 through month 24 (termed week 28+ infection), viral-load set point (mean plasma HIV-1 RNA level 10 to 20 weeks after diagnosis), and safety. The 6-plasmid DNA vaccine (expressing clade B Gag, Pol, and Nef and Env proteins from clades A, B, and C) was administered at weeks 0, 4, and 8. The rAd5 vector boost (expressing clade B Gag-Pol fusion protein and Env glycoproteins from clades A, B, and C) was administered at week 24. ResultsIn April 2013, the data and safety monitoring board recommended halting vaccinations for lack of efficacy. The primary analysis showed that week 28+ infection had been diagnosed in 27 participants in the vaccine group and 21 in the placebo group (vaccine efficacy, -25.0%; 95% confidence interval, -121.2 to 29.3; P=0.44), with mean viral-load set points of 4.46 and 4.47 HIV-1 RNA log(10) copies per milliliter, respectively. Analysis of all infections during the study period (41 in the vaccine group and 31 in the placebo group) also showed lack of vaccine efficacy (P=0.28). The vaccine regimen had an acceptable side-effect profile. Conclusions The DNA/rAd5 vaccine regimen did not reduce either the rate of HIV-1 acquisition or the viral-load set point in the population studied. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00865566.)
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The contribution of host T-cell immunity and HLA class I alleles to the control of human immunodeficiency virus (HIV-1) replication in natural infection is widely recognized. We assessed whether vaccine-induced T-cell immunity, or expression of certain HLA alleles, impacted HIV-1 control after infection in the Step MRKAd5/HIV-1 gag/pol/nef study. Vaccine-induced T cells were associated with reduced plasma viremia, with subjects targeting ≥3 gag peptides presenting with half-log lower mean viral loads than subjects without Gag responses. This effect was stronger in participants infected proximal to vaccination and was independent of our observed association of HLA-B*27, –B*57 and –B*58:01 alleles with lower HIV-1 viremia. These findings support the ability of vaccine-induced T-cell responses to influence postinfection outcome and provide a rationale for the generation of T-cell responses by vaccination to reduce viremia if protection from acquisition is not achieved. Clinical trials identifier: NCT00095576.
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Background. We report the first-in-human safety and immunogenicity assessment of a prototype Ad26 vector-based human immunodeficiency virus (HIV) vaccine in humans. Methods. Sixty Ad26-seronegative, healthy, HIV-uninfected subjects were enrolled in a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 study. Five groups of 12 subjects received 10⁹–10¹¹ vp of the Ad26-EnvA vaccine (N = 10/group) or placebo (N = 2/group) at weeks 0 and 24 or weeks 0, 4, and 24. Safety and immunogenicity were assessed. Results. Self-limited reactogenicity was observed after the initial immunization at the highest (10¹¹ vp) dose. No product-related SAEs were observed. All subjects who received the Ad26-EnvA vaccine developed Ad26 NAb titers, EnvA-specific enzyme-linked immunosorbent assays (ELISA) titers, and EnvA-specific enzyme-linked immunospot assays (ELISPOT) responses. These responses persisted at week 52. At week 28 in the 10⁹, 10¹⁰, 10¹¹ vp 3-dose and the 10¹⁰ and 5 × 10¹⁰ vp 2-dose groups, geometric mean EnvA ELISA titers were 6113, 12 470, 8545, 3470, and 9655 and mean EnvA ELISPOT responses were 397, 178, 736, 196, and 1311 SFC/10⁶ peripheral blood mononuclear cells, respectively. Conclusion. This Ad26 vectored vaccine was generally safe and immunogenic at all doses tested. Reactogenicity was minimal with doses of 5 × 10¹⁰ vp or less. Ad26 is a promising new vaccine vector for HIV-1. Clinical Trials Registration. NCT00618605.
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Background. Adenovirus serotype 26 (Ad26) has been developed as a novel candidate vaccine vector for human immunodeficiency virus type 1 (HIV-1) and other pathogens. The primary safety and immunogenicity data from the Integrated Preclinical/Clinical AIDS Vaccine Development Program (IPCAVD) 001 trial, the first-in-human evaluation of a prototype Ad26 vector-based vaccine expressing clade A HIV-1 Env (Ad26.ENVA.01), are reported concurrently with this article. Here, we characterize in greater detail the humoral and cellular immune responses elicited by Ad26.ENVA.01 in humans. Methods. Samples from the IPCAVD 001 trial were used for humoral and cellular immunogenicity assays. Results. We observed a dose-dependent expansion of the magnitude, breadth, and epitopic diversity of Env-specific binding antibody responses elicited by this vaccine. Antibody-dependent cell-mediated phagocytosis, virus inhibition, and degranulation functional activity were also observed. Env-specific cellular immune responses induced by the vaccine included multiple CD8⁺ and CD4⁺ T-lymphocyte memory subpopulations and cytokine secretion phenotypes, although cellular immune breadth was limited. Baseline vector-specific T-lymphocyte responses were common but did not impair Env-specific immune responses in this study. Conclusion. Ad26.ENVA.01 elicited a broad diversity of humoral and cellular immune responses in humans. These data support the further clinical development of Ad26 as a candidate vaccine vector. Clinical Trials Registration. NCT00618605.
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In the RV144 trial, the estimated efficacy of a vaccine regimen against human immunodeficiency virus type 1 (HIV-1) was 31.2%. We performed a case-control analysis to identify antibody and cellular immune correlates of infection risk. In pilot studies conducted with RV144 blood samples, 17 antibody or cellular assays met prespecified criteria, of which 6 were chosen for primary analysis to determine the roles of T-cell, IgG antibody, and IgA antibody responses in the modulation of infection risk. Assays were performed on samples from 41 vaccinees who became infected and 205 uninfected vaccinees, obtained 2 weeks after final immunization, to evaluate whether immune-response variables predicted HIV-1 infection through 42 months of follow-up. Of six primary variables, two correlated significantly with infection risk: the binding of IgG antibodies to variable regions 1 and 2 (V1V2) of HIV-1 envelope proteins (Env) correlated inversely with the rate of HIV-1 infection (estimated odds ratio, 0.57 per 1-SD increase; P=0.02; q=0.08), and the binding of plasma IgA antibodies to Env correlated directly with the rate of infection (estimated odds ratio, 1.54 per 1-SD increase; P=0.03; q=0.08). Neither low levels of V1V2 antibodies nor high levels of Env-specific IgA antibodies were associated with higher rates of infection than were found in the placebo group. Secondary analyses suggested that Env-specific IgA antibodies may mitigate the effects of potentially protective antibodies. This immune-correlates study generated the hypotheses that V1V2 antibodies may have contributed to protection against HIV-1 infection, whereas high levels of Env-specific IgA antibodies may have mitigated the effects of protective antibodies. Vaccines that are designed to induce higher levels of V1V2 antibodies and lower levels of Env-specific IgA antibodies than are induced by the RV144 vaccine may have improved efficacy against HIV-1 infection.
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Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV(SME543) Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection against repetitive, intrarectal SIV(MAC251) challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post-infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys.
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Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death. As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01). The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.).
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In July 1996, researchers, policymakers, and activists involved in the fight against HIV-AIDS met in Vancouver, Canada, for the 11th International Conference on AIDS. During that historic meeting, practitioners and patients heard evidence regarding a powerful weapon to stop the relentless onslaught of the human immunodeficiency virus (HIV): combination antiretroviral therapy (ART), with a protease inhibitor as the centerpiece of the regimen. In the nearly 20 years since that watershed meeting, the early promise of durable effects from combination therapy has been realized for many patients: between 2000 and 2014, the rollout of ART saved an estimated 7.8 million lives . . .
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Background. A vaccine is needed to prevent human immunodeficiency virus type 1 (HIV-1) infection. Methods. A double-blind, randomized trial of a recombinant HIV-1 envelope glycoprotein subunit (rgp120) vaccine was conducted among men who have sex with men and among women at high risk for heterosexual transmission of HIV-1. Volunteers received 7 injections of either vaccine or placebo (ratio, 2:1) over 30 months. The primary end point was HIV-1 seroconversion over 36 months. Results. A total of 5403 volunteers (5095 men and 308 women) were evaluated. The vaccine did not prevent HIV-1 acquisition: infection rates were 6.7% in 3598 vaccinees and 7.0% in 1805 placebo recipients; vaccine efficacy (VE) was estimated as 6% (95% confidence interval, -17% to 24%). There were no significant differences in viral loads, rates of antiretroviral-therapy initiation, or the genetic characteristics of the infecting HIV-1 strains between treatment arms. Exploratory subgroup analyses showed nonsignificant trends toward efficacy in preventing infection in the highest risk (VE, 43%; n = 247) and nonwhite (VE, 47%; n = 914) volunteers (P = .10, adjusted for multiple subgroup comparisons). Conclusions. There was no overall protective effect. The efficacy trends in subgroups may provide clues for the development of effective immunization approaches.
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The ultimate solution to the global HIV-1 epidemic will probably require the development of a safe and effective vaccine. Multiple vaccine platforms have been evaluated in preclinical and clinical trials, but given the disappointing results of clinical efficacy studies so far, novel vaccine approaches are needed. In this Opinion article, we discuss the scientific basis and clinical potential of novel adenovirus and cytomegalovirus vaccine vectors for HIV-1 as two contrasting but potentially complementary vector approaches. Both of these vector platforms have demonstrated partial protection against stringent simian immunodeficiency virus challenges in rhesus monkeys using different immunological mechanisms.
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The numbers of AIDS-related deaths and new HIV infections have decreased dramatically, thanks to prevention and treatment tools. But to control the pandemic more quickly and sustain the success, a safe and at least moderately effective vaccine is essential. In the past decade, according to the 2013 Global Report of the Joint United Nations Program on HIV/AIDS (UNAIDS), the numbers of AIDS-related deaths and new human immunodeficiency virus (HIV) infections have fallen by about one third from their peaks accomplishments made possible by the accelerated implementation of effective prevention and treatment tools. Of particular note, the scale-up of antiretroviral therapy (ART) averted 5.4 million deaths in low- and middle-income countries between 1995 and 2012. HIV prevention efforts have expanded from a narrow agenda of providing condoms and clean needles to use of a comprehensive toolkit of preventive interventions ...
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The global diversity of HIV-1 represents a critical challenge facing HIV-1 vaccine development. HIV-1 mosaic antigens are bioinformatically optimized immunogens designed for improved coverage of HIV-1 diversity. However, the protective efficacy of such global HIV-1 vaccine antigens has not previously been evaluated. Here, we demonstrate the capacity of bivalent HIV-1 mosaic antigens to protect rhesus monkeys against acquisition of infection following heterologous challenges with the difficult-to-neutralize simian-human immunodeficiency virus SHIV-SF162P3. Adenovirus/poxvirus and adenovirus/adenovirus vector-based vaccines expressing HIV-1 mosaic Env, Gag, and Pol afforded a significant reduction in the per-exposure acquisition risk following repetitive, intrarectal SHIV-SF162P3 challenges. Protection against acquisition of infection correlated with vaccine-elicited binding, neutralizing, and functional nonneutralizing antibodies, suggesting that the coordinated activity of multiple antibody functions may contribute to protection against difficult-to-neutralize viruses. These data demonstrate the protective efficacy of HIV-1 mosaic antigens and suggest a potential strategy for the development of a global HIV-1 vaccine. PAPERCLIP:
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Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for HIV-1 and other pathogens have been shown to be limited by high titers of Ad5 neutralizing antibodies (NAbs) in the developing world. Alternative serotype rAd vectors have therefore been constructed. Here we report Ad5, Ad26, Ad35, and Ad48 NAb titers in 4381 individuals from North America, South America, sub-Saharan Africa, and Southeast Asia. As expected, Ad5 NAb titers were both frequent and high magnitude in sub-Saharan Africa and Southeast Asia. In contrast, Ad35 NAb titers proved infrequent and low in all regions studied, and Ad48 NAbs were rare in all regions except East Africa. Ad26 NAbs were moderately common in adults in sub-Saharan Africa and Southeast Asia, but Ad26 NAb titers proved markedly lower than Ad5 NAb titers in all regions, and these relatively low Ad26 NAb titers did not detectably suppress the immunogenicity of 4×10(10)vp of a rAd26-Gag/Pol/Env/Nef vaccine in rhesus monkeys. These data inform the clinical development of alternative serotype rAd vaccine vectors in the developing world.
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The MRKAd5 HIV-1 gag/pol/nef subtype B vaccine was designed to elicit T-cell-mediated immune responses capable of providing complete or partial protection from HIV-1 infection or a decrease in viral load after acquisition. We aim to assess the safety and efficacy of the vaccine in South Africa, where the major circulating clade is subtype C. We did a phase 2b double-blind, randomised test-of-concept study in sexually active HIV-1 seronegative participants at five sites in South Africa. Randomisation was by a computer-generated random number sequence. The vaccine and placebo were given by intramuscular injection on a 0, 1, 6 month schedule. Our coprimary endpoints were a vaccine-induced reduction in HIV-1 acquisition and viral-load setpoint. These endpoints were assessed independently in the modified intention-to-treat (MITT) cohort with two-tailed significance tests stratified by sex. We assessed immunogenicity by interferon-γ ELISPOT in peripheral-blood mononuclear cells. After the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrolment and vaccination in our study was halted, treatment allocations were unmasked, and follow-up continued. This study is registered with the South Africa National Health Research Database, number DOH-27-0207-1539, and ClinicalTrials.gov, number NCT00413725. 801 of a scheduled 3000 participants, of whom 360 (45%) were women, were randomly assigned to receive either vaccine or placebo. 445 participants (56%) had adenovirus serotype 5 (Ad5) titres greater than 200, and 129 men (29%) were circumcised. 34 MITT participants in the vaccine group were diagnosed with HIV-1 (incidence rate 4·54 per 100 person-years) and 28 in the placebo group (3·70 per 100 person-years). There was no evidence of vaccine efficacy; the hazard ratio adjusted for sex was 1·25 (95% CI 0·76-2·05). Vaccine efficacy did not differ by Ad5 titre, sex, age, herpes simplex virus type 2 status, or circumcision. The geometric mean viral-load setpoint was 20,483 copies per mL (n=33) in the vaccine group and 34,032 copies per mL (n=28) in the placebo group (p=0·39). The vaccine elicited interferon-γ-secreting T cells that recognised both clade B (89%) and C (77%) antigens. The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint; however, stopping our trial early probably compromised our ability to draw conclusions. The high incidence rates noted in South Africa highlight the crucial need for intensified efforts to develop an efficacious vaccine. The US National Institute of Allergy and Infectious Disease and Merck and Co Inc.