Human Vaccines and Immunotherapeutics

Published by Taylor & Francis
Online ISSN: 2164-554X
Print ISSN: 2164-5515
Publications
Recommended and minimum acceptable ages for routine immunizations in the expanded program for immunizations (2002-2007) in Pakistan 
Immunization completion in children aged 0-5 y old, 2002-2007 in Pakistan 
Determinants of Immunization completion in children aged 0-5 y old, 2002-2007 in Pakistan 
Background: Immunization coverage data and determinants for completion are not well described for Pakistan. This study determines immunization coverage rates and timeliness based on the 2006-07 Pakistan Demographic and Health Survey (DHS) and identifies determinants for completion of immunizations. Methods: DHS data from 9177 randomly selected households from across Pakistan were analyzed to assess immunization coverage and timeliness for children aged 0-5 years, and to investigate determinants of immunization completion through logistic regressions. Results: The proportion of children immunized for a third dose of the oral poliovirus vaccine (OPV3) was 80.3%, and combination diphtheria, tetanus, and pertussis vaccines (DTP3) was 55.9%. Measles coverage was 62.5%. Late immunizations were most likely to occur for third doses of the OPV (65.5%) and DTP series (65.5%). Early doses were most likely to be administered for measles (21.9%). The proportion of children not immunized for any vaccine was 6.2%. Receiving a dose of maternal tetanus was a major determinant for immunization completion for OPV3 (OR 1.35, 95% CI: 1.14-1.60), DTP3 (OR 2.54, 95% CI: 2.13-3.02), and measles (OR 2.78, 95% CI: 2.27-3.40). Other independent variables associated with improved immunization completion included higher household wealth and maternal education. Conclusion: Poor routine immunization coverage and timeliness were identified through the DHS in Pakistan. Encouraging maternal tetanus uptake among women of child-bearing age and greater integration of immunization services with antenatal care may help improve childhood immunization completion.
 
Two novel methods of dengue virus inactivation using iodonaphthyl azide (INA) and aminomethyl trioxsalen (AMT) were compared with traditional virus inactivation by formaldehyde. The AMT inactivated dengue-2 virus retained its binding to a panel of 5 monoclonal antibodies specific for dengue-2 envelope protein, whereas inactivation by formaldehyde and INA led to 30-50% decrease in binding. All three inactivated viruses elicited high level virus neutralizing antibodies in vaccinated mice. However, only mice vaccinated with AMT inactivated virus mounted T cell responses similar to live, uninactivated virus.
 
Hepatitis B (HBV) virus infects the liver, and upon chronic infection, can cause liver cirrhosis and hepatocellular carcinoma. Despite universal vaccination programs against the virus, HBV still affects over 2 billion people worldwide, with over 240 million developing a chronic infection. While current alum-adjuvanted vaccines have shown efficacy in promoting seroprotection in healthy adults, 5-10% of immune-competent populations fail to achieve long-lasting seroprotection from these formulations. Furthermore, a large proportion of immunocompromised patients fail to achieve seroprotective antibody titers after receiving these vaccines. A novel vaccine candidate, HEPLISAV™, uses immunostimulatory sequences (ISS), in their formulation that helps induce a robust humoral and cell mediated immunity against HBV. In Phase III clinical trials, HEPLISAV™ has been shown to elicit seroprotective antibody titers with fewer immunizations. Similar safety profiles are demonstrated when compared with current HBV vaccines. For these reasons, HEPLISAV™ is an attractive vaccine to combat this global disease.
 
Purpose: Since March 2007, the Standing Committee on Vaccination (STIKO) recommends HPV vaccination for all 12-17 y-old females in Germany. In the absence of an immunization register, we aimed at assessing HPV-vaccination coverage and knowledge among students in Berlin, the largest city in Germany, to identify factors influencing HPV-vaccine uptake. Methods: Self-administered questionnaires were distributed to 10th grade school students in 14 participating schools in Berlin to assess socio-demographic characteristics, knowledge, and statements on vaccinations. Vaccination records were reviewed. Multivariable statistical methods were applied to identify independent predictors for HPV-vaccine uptake among female participants. Results: Between September and December 2010, 442 students completed the questionnaire (mean age 15.1; range 14-19). In total 281/442 (63.6%) students specified HPV correctly as a sexually transmitted infection. Of 238 participating girls, 161 (67.6%) provided their vaccination records. Among these, 66 (41.0%) had received the recommended three HPV-vaccine doses. Reasons for being HPV-unvaccinated were reported by 65 girls: Dissuasion from parents (40.2%), dissuasion from their physician (18.5%), and concerns about side-effects (30.8%) (multiple choices possible). The odds of being vaccinated increased with age (Odds Ratio (OR) 2.19, 95% Confidence Interval (CI) 1.16, 4.15) and decreased with negative attitude toward vaccinations (OR = 0.33, 95%CI 0.13, 0.84). Conclusions: HPV-vaccine uptake was low among school girls in Berlin. Both, physicians and parents were influential regarding their HPV-vaccination decision even though personal perceptions played an important role as well. School programs could be beneficial to improve knowledge related to HPV and vaccines, and to offer low-barrier access to HPV vaccination.
 
We previously reported higher anti-HPV-16 and -18 immune responses induced by HPV-16/18 vaccine compared with HPV-6/11/16/18 vaccine at Month 7 (one month after completion of full vaccination series) in women aged 18-45 years in an observer-blind study NCT00423046; the differences of immune response magnitudes were maintained up to Month 24. Here we report follow-up data through Month 48. At Month 48, in according-to-protocol cohort for immunogenicity (seronegative and DNA-negative for HPV type analyzed at baseline), geometric mean titers of serum neutralizing antibodies were 2.0- to 5.2-fold higher (HPV-16) and 8.6- to 12.8-fold higher (HPV-18) in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. The majority of women in both vaccine groups remained seropositive for HPV-16. The same trend was observed for HPV-18 in HPV-16/18 vaccine group; however, seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably, particularly in the older age groups. In the total vaccinated cohort (regardless of baseline serological and HPV-DNA status), anti-HPV-16 and -18 neutralizing antibody levels induced by HPV-16/18 vaccine were higher than those induced by HPV-6/11/16/18 vaccine. CD4+ T-cell response for HPV-16 and HPV-18 was higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. Memory B-cell responses appeared similar between vaccine groups. Both vaccines were generally well tolerated. Overall, the higher immune response observed with the HPV-16/18 vaccine was maintained up to Month 48. A head-to-head study incorporating clinical endpoints would be required to confirm whether the observed differences in immune response between the vaccines influence the duration of protection they provided.
 
The aim of this study was to evaluate hepatitis B surface antibody (anti-HBs) levels one year after hepatitis B booster vaccination in anti-HBs-negative(<10mIU/mL) children 11-15 years after primary vaccination. Anti-HBs titers were examined in 235 children who were negative for hepatitis B surface antigen (HBsAg), anti-HBs, and hepatitis B core antibody (anti-HBc). The children were then divided into three groups based on their anti-HBs levels pre-booster: Group I, <0.1mIU/mL; Group II, 0.1 to <1.0mIU/mL; and Group III, 1.0 to <10.0mIU/mL. They were vaccinated with three doses of hepatitis B vaccine (0-1-6 month, 20ug), and anti-HBs levels were measured. One month after the first dose, the anti-HBs positive rates (≥10mIU/mL) in Groups I-III were 56.14%, 83.61% and 100%. One month after the third dose, the anti-HBs-positive rates in Groups I-III were 96.49%, 98.36% and 100%. One year after the third dose, the anti-HBs-positive rates in Groups I-III were 73.68%, 75.41% and 98.29%, respectively. Protective levels declined more rapidly for those with lower titers. Children with pre-booster anti-HBs titers of 1-9.9mIU/mL might not need any booster dose, and the children with pre-booster titers of 0.1-0.9 and <0.1mIU/mL might need more than one dose booster vaccination.
 
The combined diphtheria-tetanus-acellular pertussis-hepatitis B-poliomyelitis/Haemophilus influenza vaccine (DTPa-HBV-IPV/Hib: Infanrix™ hexa, GlaxoSmithKline Vaccines) is used for primary vaccination of infants in a range of schedules world-wide. Antibody persistence after four DTPa-HBV-IPV/Hib doses in the first two years of life has been documented, but long-term persistence data following the 3, 5, 11-12 months (3-5-11) infant vaccination schedule, employed for example in Nordic countries, are limited. We assessed antibody persistence in 57 five-year-old children who had received either DTPa-HBV-IPV/Hib or DTPa-IPV/Hib (Infanrix™-IPV/Hib, GlaxoSmithKline Vaccines) in the 3-5-11 schedule. Among DTPa-HBV-IPV/Hib recipients, 7/12 retained seroprotective antibody concentrations for diphtheria, 10/12 for tetanus, 5/12 for hepatitis and 10/12 for Hib. Detectable antibodies were observed for 0/12 children for pertussis toxin (PT), 12/12 for filamentous haemagglutinin (FHA) and 8/12 for pertactin (PRN). Among DTPa-IPV/Hib recipients, 28/45 retained seroprotective anti-diphtheria concentrations, 34/44 for tetanus and 40/45 for Hib. Detectable antibodies were observed for 9/45 children for PT, 41/45 for FHA and 34/45 for PRN. Antibody persistence in DTPa-HBV-IPV/Hib and DTPa-IPV/Hib-vaccinees appeared similar in 5 year olds to that previously observed in children of a similar age who had received four prior doses of DTPa-HBV-IPV/Hib (or DTPa-IPV/Hib). As in subjects primed with four prior doses, we observed that antibodies markedly declined by 5 years of age, calling for the administration of a pre-school booster dose in order to ensure continued protection against pertussis.
 
Phacilitates 1st Partnering event for Vaccine Emerging Markets brought together approximately 100 attendees from developed and developing world vaccine manufacturers, leading non-profit organizations and industry suppliers. The goal was to discuss the vaccine needs in the developing world and how these needs can be met by leveraging collaboration and partnership models, by improving access to existing, new and next generation vaccines, by using novel technologies to drive competitive advantage and economics of vaccine manufacturing and by investing in localized capacity, including capacity for pandemic vaccines. The present article summarizes insights out of 30 oral contributions on how quality and capacity requirements can be balanced with cost by using novel manufacturing technologies and operating models.
 
The conference was a true forum for the Emerging Markets global vaccine community. Close to 100 senior-level representatives from large and small vaccine-related private sector firms, from the UN system (World Health Organization -WHO and Pan American Health Organization -PAHO) as well as donors (The Global Alliance for Vaccines and Immunization -GAVI and the Gates Foundation), convened in Berlin in an atmosphere of open and helpful information exchange. The great challenges involved in working in Emerging Markets were discussed; the speakers repeatedly highlighted cultural awareness and close communication as key elements for success. Nonetheless an underlying optimism and can-do attitude permeated the discussions: many among the audience are directly responsible for the historically unprecedented success in vaccine delivery to third world countries occurring over the last decade. : Chairing this plenary session was by Dr. Jon Kim Andrus, Pan American Health Organization's (PAHO) Deputy Director. He is a public health expert with over 25 years work experience in vaccines, immunization, and primary care in developing countries. The panelists were Dr. Jorge Kalil, President of the Butantan Institute, in Sao Paulo, Brazil and Lic. Abel Di Gilio, President of Sinergium Biotech, in Buenos Aires, Argentina. Both speakers have extensive experience in the building of vaccine production factories in emerging market countries, and most importantly, in building, promoting and securing, at the national and international levels, the institutional and political support necessary for sustainability and growth.
 
To evaluate antibody response induced by trivalent inactivated influenza vaccine (TIV) against circulating influenza A (H3N2) strains in healthy adults during the 2010/11 and 2011/12 seasons, a hemagglutination-inhibition (HI) assay was utilized to calculate geometric mean antibody titer (GMT), seroprotection rate (post vaccination HI titers of ≥1:40), and seroresponse rate (4-fold increase in antibody level). In the 2010/11 season, GMT increased 1.8- to 2.0-fold following the first dose of TIV against three circulating strains and 2.2-fold following the second compared to before vaccination. The seroresponse rate ranged from 22% to 26% following the first dose of TIV and from 31% to 33% following the second (n=54). The seroprotection rate increased from a range of 6% to 13% to a range of 26% to 33% following the first dose of TIV and to a range of 37% to 42% following the second (n=54). In the 2011/12 season, GMT increased 1.4-fold against A/Osaka/110/2011 and 1.8-fold against A/Osaka/5/2012. For A/Osaka/110/2011, the seroresponse rate was 29%, and the seroprotection rate increased from 26% to 55% following vaccination (n=31). For A/Osaka/5/2012, the seroresponse rate was 26%, and the seroprotection rate increased from 68% to 84% following vaccination (n=31). HI assays with reference antisera demonstrated that the strains in the 2011/12 season were antigenically distinct from vaccine strain (A/Victoria/210/2009). In conclusion, the vaccination increased the seroprotection rate against circulating H3N2 strains in the 2010/11 and 2011/12 seasons. Vaccination of TIV might have potential to induce reactive antibodies against antigenically distinct circulating H3N2 viruses.
 
Subject disposition: CONSORT diagram ATP, according-to-protocol. The Month 60 ATP cohort for immunogenicity included all evaluable subjects who received 3 vaccine doses (i.e., those meeting all eligibility criteria and complying with the procedures defined in the protocol) for whom data concerning immunogenicity endpoint measures were available. This included subjects for whom assay results were available for antibodies against at least one study vaccine antigen (HPV-16 or HPV-18) at the time point under analysis.
GMTs for (A) serum anti-HPV-16 and (B) anti-HPV-18 type-specific neutralizing antibodies at Months 6, 7, 12, 18, 24, 36, 48 and 60 (PBNA, ATP kinetic cohort; seronegative and DNA-negative for the HPV type analyzed prior to vaccination) ATP, according-to-protocol; ED 50 , effective dose producing 50% response; GMT, geometric mean titers; n, number of subjects with available results; PBNA, pseudovirion-based neutralization assay. Pink narrow dashed line, HPV-16/18 vaccine 1826 y (HPV-16 n D 27, HPV-18, n D 31); pink wide dashed line with &, HPV-16/18 vaccine 27-35 y (HPV-16 n D 36, HPV-18 n D 47); solid pink line with ~, HPV-16/18 vaccine 36-45 y (HPV-16 n D 37, HPV-18 n D 46); blue narrow dashed line, HPV-6/11/16/18 vaccine 18-26 y (HPV-16 n D 36, HPV-18 n D 46); blue wide dashed line with &, HPV-6/ 11/16/18 vaccine 27-35 y (HPV-16 n D 25, HPV-18 n D 30); solid blue line with ~, HPV-6/11/16/18 vaccine 36-45 y (HPV-16 n D 38, HPV-18 n D 43). Error bars denote 95% confidence intervals of GMTs. Dotted line, GMTs for natural infection neutralizing antibody levels as measured by PBNA in women in the total vaccinated cohort of the HPV-010 study who had cleared natural infection (prior to vaccination) [i.e., those who were seropositive and DNA-negative at Month 0]: 180.1 ED 50 for HPV-16 and 137.3 ED 50 for HPV-18. 2
Summary of safety and pregnancy outcomes from Month 0 to Month 60 (total vaccinated cohort; irrespective of serostatus and DNA status prior to vaccination) HPV-16/18 vaccine [N D 553] HPV-6/11/16/18 vaccine [N D 553] 
GMTs for (A) serum anti-HPV-16 and (B) anti-HPV-18 type-specific antibodies at Months 6, 7, 12, 18, 24, 36, 48 and 60 (ELISA, ATP kinetic cohort; seronegative and DNA-negative for the HPV type analyzed prior to vaccination) ATP, according-to-protocol; ELISA, enzymelinked immunosorbent assay; GMT, geometric mean titers; n, number of subjects with available results. Pink narrow dashed line, HPV-16/18 vaccine 18-26 y (HPV-16 n D 24, HPV-18, n D 25); pink wide dashed line with &, HPV-16/18 vaccine 27-35 y (HPV-16 n D 23, HPV-18 n D 34); solid pink line with ~, HPV-16/18 vaccine 36-45 y (HPV-16 n D 25, HPV-18 n D 32); blue narrow dashed line, HPV-6/11/ 16/18 vaccine 18-26 y (HPV-16 n D 32, HPV-18 n D 36); blue wide dashed line with &, HPV-6/11/16/18 vaccine 27-35 y (HPV-16 n D 17, HPV-18 n D 23); solid blue line with ~, HPV-6/11/16/18 vaccine 36-45 y (HPV-16 n D 25, HPV-18 n D 36). Error bars denote 95% confidence intervals of GMTs. Dotted line, GMTs for natural infection antibody levels (measured by ELISA) in the HPV-008 study: 29.8 ELISA units/ mL for HPV-16 and 22.6 ELISA units/mL for HPV-18. 9
Serum anti-HPV-16 and antiHPV-18 type-specific neutralizing antibody responses (by PBNA analysis) over 20 y predicted by the (A) piecewise linear model and (B) modified power-law model (total vaccinated cohort, 3 doses) ED 50 , effective dose producing 50% response; GMT, geometric mean titer; PBNA, pseudovirion-based neutralization assay. Pink narrow dashed line, HPV-16/18 vaccine 18-26 y; pink wide dashed line, HPV-16/18 vaccine 27-35 y; solid pink line, HPV-16/18 vaccine 36-45 y; blue narrow dashed line, HPV-6/11/16/18 vaccine 18-26 y; blue wide dashed line, HPV-6/11/16/18 vaccine 27-35 y; solid blue line, HPV-6/11/16/18 vaccine 36-45 y; dotted line, neutralizing antibody GMTs measured by PBNA in women in the total vaccinated cohort of the HPV-010 study who had cleared natural infection (prior to vaccination) [i.e., those who were seropositive and DNA-negative at Month 0]: 180.1 ED 50 for HPV-16 and 137.3 ED 50 for HPV18. 2 *Predicted GMTs were calculated for 20 y after the first vaccine dose.
The observer-blind, randomized, age-stratified, head-to-head study (NCT00423046) comparing immunogenicity and safety of HPV-16/18 and HPV-6/11/16/18 vaccines in healthy women aged 18-45 years was completed. Five years after vaccination, in subjects from the Month 60 according-to-protocol cohort (seronegative and DNA negative for HPV type analyzed at baseline), serum neutralizing antibody (nAb) responses induced by HPV-16/18 vaccine remained 7.8-fold (18-26-year stratum), 5.6-fold (27-35-year stratum) and 2.3-fold (36-45-year stratum) higher than those induced by HPV-6/11/16/18 vaccine for HPV-16. For HPV-18, the fold differences were 12.1, 13.0 and 7.8, respectively. At Month 60, all (100%) subjects in HPV-16/18 vaccine group and the majority (95.7%-97.5%) in HPV-6/11/16/18 vaccine group were seropositive for HPV-16. For HPV-18, the majority (98.1%-100%) of subjects in HPV-16/18 vaccine group were seropositive; however, seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably (61.1%-76.9%) across the three age strata. In the total vaccinated cohort (received ³1 dose regardless of baseline HPV serostatus and DNA status), geometric mean titers for anti-HPV-16 and anti-HPV-18 nAb were higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. Based on the five-year data, piece-wise and modified power-law models predicted a longer durability of nAb response for HPV-16/18 vaccine compared to HPV-6/11/16/18 vaccine. Beyond the differences apparent between the vaccines in terms of immunogenicity and modeled persistence of antibody responses, comparative studies including clinical endpoints would be needed to determine whether differences exist in duration of vaccine-induced protection.
 
This double-blind, randomized study evaluated the immunogenicity and safety of three production lots of the fully liquid combination DTwP-Hep-Hib vaccine, Quinvaxem (®) (Crucell, The Netherlands) in 360 healthy infants aged 42-64 d old given at 6, 10 and 14 weeks of age (Core Study). The Core Study was followed by an open-label Booster Phase evaluating immunogenicity and safety of a booster dose of Quinvaxem (®) given with either concomitant or deferred measles vaccine in 227 infants who completed the Core Study. One month after the third dose of Quinvaxem (®) immune responses reflecting seroprotection or seroconversion were observed in more than 90% of infants for all three vaccine lots. Quinvaxem (®) elicited a strong booster response as demonstrated by a large increase in antibodies against all antigens, which appeared to be unaffected by concomitant administration of the measles vaccine. Safety results were in line with previous reports for Quinvaxem (®) with no unexpected adverse events (AEs) being reported. In the Core Study and Booster Phase, Quinvaxem (®) was well tolerated. No study vaccine-related serious AEs were reported. Thus, Quinvaxem (®) was immunogenic and well-tolerated when administered to infants according to a 6-10-14 week vaccination schedule. The three production lots had consistent reactogenicity and immunogenicity profiles. The booster dose of Quinvaxem (®) was also immunogenic and safe, regardless of whether a monovalent measles vaccine was administered concomitantly or one month later.
 
H5N1 influenza candidate vaccine viruses were developed using the "6+2" approach. The hemagglutinin (HA) and neuraminidase (NA) genes were derived from the popular H5N1 virus and the remaining six internal segments were derived from the A/Puerto Rico/8/34 strain (H1N1, PR8). However, some of these candidate strains have been reported to produce relatively low yields in vaccine manufacture. In this study, we found that the NA vRNA of the A/Vietnam/1194/2004 strain (H5N1, VN1194) was poorly packaged into recombinant viruses with a backbone of PR8 genes, which resulted in the formation of defective virions that did not include the NA vRNA in the genome. Using recombinant DNA techniques, we constructed a chimeric NA gene with the coding region of VN1194 NA flanked by the packaging signal sequence of the PR8 NA gene (41 bp form the 3' end of the vRNA and 67 bp from the 5' end). The packaging of the NA vRNA was restored to normal levels in the recombinant viruses containing the chimeric NA gene. Recombinant viruses containing the chimeric NA replicated much better in chicken embryonated eggs than viruses with the wild-type NA from VN1194. These findings suggest a novel strategy to improve in ovo growth of vaccine strains and to increase the number of vaccine doses available to save people if a pandemic were to occur.
 
The 11th Annual Meeting of Association for Cancer Immunotherapy (CIMT) welcomed more than 700 scientists around the world to Mainz, Germany and continued to be the largest immunotherapy meeting in Europe. Renowned speakers from various fields of cancer immunotherapy gave lectures under CIMT2013's tag: "Advancing targeted therapies" the highlights of which are summarized in this meeting report.
 
More than 900 scientists around the word visited the 12th Annual Meeting of Association for Cancer Immunotherapy (CIMT) in Mainz, Germany from 6-8 May, 2014. Recent advancements in various specific fields of cancer immunotherapy was discussed in this Europe`s largest meeting of its kind under the motto "Next Waves in Cancer Immunotherapy" the highlights of which are summarized in this meeting report.
 
HPV vaccination is expected to reduce the incidence of cervical cancer. The greatest and the earliest health gains will be ensured by high vaccine coverage among all susceptible people. The high costs and the risk of a reduced cost/effectiveness ratio in sexually active girls still represent the main obstacles for a more widespread use of HPV vaccination in many countries. Data on the rate, risk factors, and HPV types in sexually active women could provide information for the evaluation of vaccination policies extended to broader age cohorts. Sexually active women aged 13–26 years enrolled in an Italian cohort study were screened for cervical HPV infections; HPV-DNA positive samples were genotyped by InnoLipa HPV Genotyping Extra or by RFLP genotype analysis. Among the 796 women meeting the inclusion criteria, 10.80% (95% CI 8.65–12.96) were HPV-DNA infected. Age >18 years, lifetime sexual partners >1, and history of STIs were associated to higher risk of HPV infection in the multivariable models adjusted for age, lifetime sexual partners, and time of sexual exposure. The global prevalence of the four HPV vaccine-types was 3.02% (95% CI 1.83–4.20) and the cumulative probability of infection from at least one vaccine-type was 12.82% in 26-years-old women and 0.78% in 18-years-old women. Our data confirm most of the previously reported findings on the risk factors for HPV infections. The low prevalence of the HPV vaccine-types found may be useful for the evaluation of the cost/efficacy and the cost/effectiveness of broader immunization programs beyond the 12-years-old cohort.
 
A hepatitis A+B vaccine vaccination program of 12-year-olds was introduced in Catalonia in 1998. The aim of this study was to investigate the evolution of hepatitis A outbreaks in Catalonia and estimate the preventable fraction of cases associated with outbreaks as a measure of the impact of the vaccination program. Hepatitis A outbreaks reported to the Health Department between 1991 and 2012 were analyzed. The incidence rates of outbreaks, outbreak-associated cases and hospitalizations were calculated. The preventable fraction (PF) and 95% confidence intervals (CI) were estimated for the whole study period (pre-vaccination and post-vaccination) and the post-vaccination period. One-hundred-eight (108) outbreaks (rate of 2.21 per 10 (6) persons-year) were reported in the pre-vaccination period and 258 outbreaks (rate of 2.82 per 10 (6) persons-year) in the post-vaccination period. The rate of cases associated with outbreaks was 1.52 per 10 (5) persons-year in the pre-vaccination period and 1.28 per 10 (5) persons-year in the post-vaccination period. Hospitalization rates were 0.08 and 0.75 per 10 (6) persons-year, respectively. The number of person-to-person outbreaks whose index case was a school contact decreased in the post-vaccination period (aOR 2.72; 95%CI 1.35-5.48), but outbreaks whose index case was a man who has sex with men (MSM) or an immigrant increased. The PF of all outbreak-associated cases was 6.46% (95%CI 3.11-9.82) and the highest PF was in the 15-24 years age group (42.53%; 95%CI 29.30-55.75). In the 0-4 years age group, the PF was 18.35% (95%CI 9.59-27.11), suggesting a protective herd effect in unvaccinated subjects. Vaccination of immigrants traveling to endemic countries and MSM should be reinforced.
 
Summary information from the identified studies
Summary of estimated efficacy of PPV23 and PCV13 in the studies PPV23 PCV13
The incidence rate of IPD and NPP in the studies (rate per 100,000)
The 13-valent pneumococcal conjugated vaccine (PCV13) is already recommended for some adult groups and is being considered for wider use in many countries. In order to identify the strengths and limitations of the existing economic evaluation studies of PCV13 in adults and the elderly a literature review was conducted. The majority of the studies identified (9 out of 10) found that PCV13 was cost-effective in adults and/or the elderly. However, these results were based on assumptions that could not always be informed by robust evidence. Key uncertainties included the efficacy of PCV13 against non-invasive pneumonia and the herd immunity effect of childhood vaccination programs. Emerging trial evidence on PCV13 in adults from the Netherlands offers the ability to parameterize future economic evaluations with empirical efficacy data. However, it is important that these estimates are used thoughtfully when they are transferred to other settings.
 
Participant demographics of the evaluable immunogenicity population 
Pneumococcal IgG GMcs 1 mo after PcV13 without or with alPO 4 (evaluable immunogenicity population)
Pneumococcal immune responses 1 mo after PcV13 and PPsV23 (evaluable immunogenicity population) 
Immune responses after each vaccination in the vaccine sequence PcV13/PPsV23/PcV13 
systemic events reported within 14 d after vaccination 
This randomized open-label trial was designed to provide preliminary immunogenicity and safety data to support development of the pediatric 13-valent pneumococcal conjugate vaccine (PCV13) for adults. The aims were to: identify an age-appropriate PCV13 formulation, i.e., with (n = 309) or without (n = 304) aluminum phosphate (AlPO 4); compare the selected PCV13 formulation (n = 309) with 23-valent pneumococcal polysaccharide vaccine (PPSV23; n = 301); and, together with an extension study, assess sequential use of pneumococcal vaccines at 1-year intervals in adults aged ≥65 years (n = 105) not pre-vaccinated with PPSV23. Immune responses were measured by ELISA and opsonophagocytic activity assays 1 month postvaccination. Immunoglobulin G responses elicited by PCV13 with AlPO 4 and PCV13 without AlPO 4 were similar for the majority, and noninferior for all PCV13 serotypes. PCV13 with AlPO 4 was generally more reactogenic, with reactions mainly mild or moderate. Thus, PCV13 with AlPO4 (hereafter PCV13) became the selected formulation. Immune responses to PCV13 were noninferior for all but one serotype and for most PCV13 serotypes superior to PPSV23. Vaccine sequence assessments showed that for PCV13/PPSV23, the initial PCV13 dose generally enhanced responses to a subsequent PPSV23 dose, compared with PPSV23 alone. For PCV13/PCV13, a second dose did not enhance the first dose response when given after 1 year. For PCV13/PPSV23/PCV13, priming with PCV13 (vaccination 1) did not protect against lower responses induced by PPSV23 to subsequent PCV13 (vaccination 3). In conclusion, the pediatric PCV13 formulation with AlPO 4 is well-tolerated and immunogenic in adults, is generally more immunogenic than PPSV23, and subsequent vaccination with PPSV23 is possible if required.
 
Distribution of the population residing in acM (spain) according to study variables 
Influenza vaccination coverage for the 2012/13 campaign among the population residing in acM (spain) according to study variables 
Factors associated to Influenza vaccination uptake for the 2012/13 campaign among the population residing acM (spain) according to age groups 
We aim to determine 2012–13 seasonal influenza vaccination coverage. Data were analyzed by age group and by coexistence of concomitant chronic conditions. Factors associated with vaccine uptake were identified. We also analyze a possible trend in vaccine uptake in post pandemic seasons. We used computerized immunization registries and clinical records of the entire population of the Autonomous Community of Madrid, Spain (6 284 128 persons) as data source. A total of 871 631 individuals were vaccinated (13.87%). Coverage for people aged ≥ 65 years was 56.57%. Global coverage in people with a chronic condition was 15.7% in children and 18.69% in adults aged 15–59 years. The variables significantly associated with a higher likelihood of being vaccinated in the 2012–13 campaign for the age groups studied were higher age, being Spanish-born, higher number of doses of seasonal vaccine received in previous campaigns, uptake of pandemic vaccination, and having a chronic condition. We conclude that vaccination coverage in persons aged <60 years with chronic conditions is less than acceptable. The very low coverage among children with chronic conditions calls for urgent interventions. Among those aged ≥60 years, uptake is higher but still far from optimal and seems to be descending in post-pandemic campaigns. For those aged ≥65 years the mean percentage of decrease from the 2009/10 to the actual campaign has been 12%. Computerized clinical and immunization registers are useful tools for providing rapid and detailed information about influenza vaccination coverage in the population.
 
Italian national recommendations for PcV13 immunization schedule in new- borns and in children <60 mo of age 
Pneumococcal disease epidemiology has changed after introduction of pneumococcal conjugate vaccines. Seven-valent vaccine (PCV7) has been effective in reducing invasive pneumococcal disease (IPD). In Europe, PCV13 effectiveness was estimated at 78% (95% CI: -18-96%) for 2-priming doses. In Italy, PCV7 was introduced in 2006 in the childhood immunization schedule and replaced with PCV13 in 2010. In Apulia, vaccination coverage has reached 95.1% (birth-cohort 2010). We estimated PCV program effectiveness and its impact on S.pneumoniae diseases. PCV Effectiveness We used the screening method. We calculated the Proportion of Population Vaccinated from immunization registries and detected cases through a laboratory-confirmed surveillance among hospitalized children ≤60 mo. A confirmed IPD case was a child with PCR positive for S.pneumoniae. Differences among children were assessed with the Chi-square or the Fisher exact test (P value<0.05). PCV Impact: We constructed time series using outcome-specific Poisson regression models: hospitalization rate in pre-PCV era and hospitalization Risk Ratios (RRs) with 95% CIs for both PCV7 and PCV7/PCV13 shifting era. We calculated hospitalization RR with 95% CIs comparing pre-PCV years with vaccination period. The PCV effectiveness was 84.3%(95% CI: 84.0-84.6%). In May 2010-January 2013, we enrolled 159 suspected IPD of whom four were confirmed. Two (fully vaccinated) were caused by serotype 9V, one (not vaccinated) by serotype 3, one (vaccinated with 2 PCV13 doses) by 15B/C. The most important reduction was for pneumococcal pneumonia (RR: 0.43, 95% CI: 0.21-0.90). The PCV program show promising results in terms of both PCV13 effectiveness and its impact in reducing IPD in children<5 y.
 
avoided costs and cases for the first targeted group 
Pneumococcal pneumonia has a high clinical burden in terms of morbidity, mortality and hospitalization rate, with heavy implications for worldwide health systems. In particular, higher incidence and mortality rates of community-acquired pneumonia (CAP) cases, with related costs, are registered among elderly. This study aimed to an economic evaluation about the immunization with PCV13 in the adult population in Campania region, South Italy. For this purpose we performed, considering a period of 5 y, a budget impact analysis (BIA) and a cost-effectiveness analysis which considered 2 scenarios of immunization compared with lack of immunization for 2 targeted cohorts: first, the high risk subjects aged 50–79 y, and second the high risk individuals aged 50–64 y, together with all those aged 65 y. Regarding the first group, the decrease of pneumonia could give savings equal to €29 005 660, while the immunization of the second cohort could allow savings equal to €10 006 017. The economic evaluation of pneumococcal vaccine for adult groups represents an essential instrument to support health policies. This study showed that both hypothesized immunization strategies could produce savings. Obtained results support the use of pneumococcal conjugate vaccine for adults. This strategy could represent a sustainable and savings-producer health policy.
 
Few epidemiological data are available after the introduction of the 13-valent pneumococcal vaccine (PCV13) in 2010. We performed repeat nasopharyngeal swabs and evaluated the serotype distribution of Streptococcus pneumoniae (SP) and its association with PCV13 vaccine status in healthy Italian children aged 3-59 months. SP serotypes were assessed by the Quellung reaction. 618 children appropriately (28%) or incompletely (72%) vaccinated for age with PCV13 were available at baseline (T0). 515 were re-evaluated at 6 months from baseline (T6) and 436 at 12 months from baseline (T12). The percentage of appropriately vaccinated subjects at T0, T6 and T12 was 28%, 67% and 92%, respectively. Random effects logistic regression models with robust 95% confidence intervals was used to estimate the time-related changes in SP and PCV13 carriage and marginal probabilities were obtained from such models. The age-corrected probability of SP carriage was 0.31 (95% CI 0.22 - 0.41) at T0, 0.32 (0.24 - 0.40) at T6 and 0.28 (0.20 - 0.35) at T12. The probability of PCV13 serotypes carriage was 0.025 (0.001 - 0.050) at T0, 0.018 (0.001 - 0.039) at T6 and 0.010 (0.001 - 0.023) at T12. A decrease in PCV13 serotypes and a shift in non-PCV13 serotypes colonization was observed. In particular, the 15A serotype accounted for 4%, 8% and 23% of SP isolates at T0, T6 and T12, respectively. In conclusion, the benefits of the PCV13 vaccination on SP carriage increase with increasing coverage rates. The shift of SP isolates towards non-PCV13 serotypes needs to be studied further.
 
safety and tolerability of a 13-valent Pneumococcal conjugate vaccine in the elderly in Liguria Region, Italy: baseline demographic characteristics of the study population 
BackgroundJump to sectionBackgroundMethodsResultsConclusionIntroductionMethodsResultsDiscussionIn September 2011 the European Medical Agency authorized the use of 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥50 years. The same occurred in the US in December 2011 when the Food and Drug Administration approved the use of PCV13 in the same target age-group with indication for the prevention of invasive pneumococcal diseases and community acquired pneumonia sustained by the serotypes contained in the vaccine. The Liguria Region, in Italy, implemented in 2013 an active and free of charge immunization strategy with PCV13 among adults affected by specific risk conditions and the elderly aged ≥70 years.MethodsJump to sectionBackgroundMethodsResultsConclusionIntroductionMethodsResultsDiscussionAn observational study was performed in order to assess the safety and tolerability of PCV13 among elderly dwelling in the metropolitan area of Genoa, the capital city of Liguria Region. Eligible subjects, who received PCV13 following the public health immunization campaign at the Local Health Unit 3 of Genoa, provided a written informed consent to take part in the study. Eight-hundred-seventy-one subjects were enrolled between October 2013 and May 2014: all were monitored by qualified healthcare personnel for at least 30 min after vaccination at the outpatient clinics, in order to assess any possible sudden reaction. The occurrence of a series of local and systemic solicited reactions and of any unsolicited Adverse Events (AEs) was monitored using a self-administered clinical diary and by regular phone contacts up to 14 and 21 d following immunization, respectively. Moreover, a 6-months follow-up following vaccination was planned in order to monitor Severe Adverse Events (SAEs).ResultsJump to sectionBackgroundMethodsResultsConclusionIntroductionMethodsResultsDiscussionNo sudden reaction occurred in vaccinees at the outpatient clinics. Pain (27.4%) was the most frequent reaction reported by subjects at the injection site, while new muscle pain (13.6%), fatigue (10.7%), and headache (9.9%) resulted the most common systemic reactions. Rates of the main reactions reported in this on-field study resulted generally lower than those registered in clinical trials performed in the elderly. The incidence of fever (2.2%) following vaccination was low at values superimposable to that reported in previous studies.ConclusionJump to sectionBackground MethodsResultsConclusion IntroductionMethods ResultsDiscussionThis observational study showed a good safety and tolerability of PCV13 among the elderly in routine clinical practice further confirming the evidence coming from clinical trials in the same age-group.
 
This open-label study was designed to assess immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) when administered to Japanese adults aged ≥50 years not previously vaccinated with 23-valent pneumococcal polysaccharide vaccine; and to compare this Japanese study population with similar study populations in the United States (US; 50-64 years age group) and European Union (EU; ≥65 years age group). Functional antibody immune responses were measured by opsonophagocytic activity assays. Immune responses in both Japanese age groups showed significant pre/postvaccination fold rises for each serotype. In the Japanese 50-64 years age group, immune responses for the majority of serotypes were significantly lower than in the ≥65 years Japanese age group, and generally lower than in the 50-64 years age group in the US study. Immune responses in the Japanese ≥65 years age group were significantly higher for the majority of serotypes when compared with the ≥65 years age group in the EU study. The safety profiles across age groups and studies were generally similar. In conclusion, PCV13 elicited robust immune responses in the Japanese study population. The unanticipated higher immune responses observed in the older age group in the Japan study are of interest and of potential benefit given the higher incidence of pneumococcal disease in older adults. PCV13 was well tolerated and safe.
 
Table 1. reactivity of a panel of monoclonal antibodies against intact and disrupted HPV VLPs eLISA reactivity of Monoclonal Antibody Panel Against Intact and Disrupted GArDASIL™ VLPs. reactivity of 0.1 ug/mL of purified mAb to 5 ug/mL of HPV L1 VLP antigen. *Intact, VLP coated buffer: 50 mM Histidine buffer + 0.5 M naCl, pH 6.2; **Disrupted = VLP coated buffer; 0.2 M sodium Carbonate buffer + 0.01 M Dtt, pH 10.6.
 
Demographic characteristics of enrolled and vaccinated tod- dlers (total vaccinated cohort) 
participant flow diagram. acWY-TT, toddlers vaccinated with one dose of MenacWY-TT; Menc-cRM, toddlers vaccinated with one dose of Menc-cRM 197 ; aTp, according to protocol; TVc, total vaccinated cohort; N, number of toddlers.
Incidence (with 95% cI) of solicited local and general symptoms occurring within four days after the first vaccination in toddlers (total vaccinated cohort). acWY-TT, toddlers vaccinated with one dose of MenacWY-TT; Menc-cRM, toddlers vaccinated with one dose of Menc-cRM 197. error bars represent 95% confidence interval.
Effective vaccines offering broad protection to toddlers, who are at high risk for invasive meningococcal disease, are needed. Here, the immunogenicity, safety and antibody persistence of the tetravalent meningococcal ACWY tetanus toxoid conjugate vaccine (MenACWY-TT) were evaluated in toddlers. Healthy participants aged 12 to 23 mo (n = 304) were randomized (3:1) to receive one dose of MenACWY-TT or a monovalent meningococcal serogroup C conjugate vaccine (MenC-CRM 197). Serum bactericidal activity was evaluated with assays using rabbit (rSBA) and human (hSBA) complement up to three years post-vaccination. MenACWY-TT was demonstrated to be non-inferior to MenC-CRM 197 in terms of immunogenicity to serogroup C, and the pre-specified immunogenicity criteria for serogroups A, W-135 and Y were met. Exploratory analyses suggested that rSBA geometric mean titers (GMTs), hSBA GMTs and proportions of toddlers with rSBA titers ≥ 1:128 and hSBA titers ≥ 1:4 and ≥ 1:8 were higher for all serogroups at one month post-vaccination with MenACWY-TT compared with MenC-CRM 197. At three years post-vaccination, at least 90.8% and 73.6% of MenACWY-TT recipients retained rSBA titers ≥ 1:8 for all serogroups and hSBA titers ≥ 1:4 for serogroups C, W-135 and Y, respectively, but the percentages of toddlers with hSBA titers ≥ 1:4 for serogroup A decreased to 21.8%. In both groups, grade 3 adverse events were infrequently reported and no serious adverse events were considered causally related to vaccination. These results suggest that one single dose of MenACWY-TT induces a robust and persistent immune response and has an acceptable safety profile in toddlers. This study has been registered at www.clinicaltrials.gov NCT00427908.
 
Demographic characteristics of enrolled and vaccinated subjects (total vaccinated cohort) 
Immunogenicity and safety of ACWY-TT compared with licensed ACWY polysaccharide vaccine (MenPS) in healthy adults, and lot-to-lot consistency of three ACWY-TT lots were evaluated in a phase 3, open, controlled study. Adults aged 18–55 y were randomized to receive ACWY-TT (one of three lots) or MenPS. Serum bactericidal antibodies (rSBA) were measured pre- and 1 mo post-vaccination. Adverse events (AEs) were assessed 4 d (solicited symptoms) and 31 d (unsolicited symptoms) post-vaccination. Serious AEs were reported up to 6 mo after vaccination. The number of vaccinated subjects was 1247 (ACWY-TT, n = 935; MenPS, n = 312). ACWY-TT lot-to-lot consistency and non-inferiority of ACWY-TT as compared with MenPS groups were demonstrated according to pre-specified criteria. The percentages of subjects with a vaccine response (VR = rSBA titer ≥ 1:32 in initially seronegative; ≥ 4-fold increase in initially seropositive) to ACWY-TT vs. MenPS were 80.1%/69.8% (serogroup A), 91.5%/ 92.0% (C), 90.2%/85.5% (W-135), 87.0%/78.8% (Y). Exploratory analyses showed that for serogroups A, W-135 and Y, VR rates and GMTs were significantly higher for ACWY-TT compared with MenPS. For each serogroup, ≥ 98.0% of subjects had rSBA titers ≥ 1:128. Grade 3 solicited AEs were reported in ≤ 1.6% of subjects in any group. The immunogenicity of ACWY-TT vaccine was non-inferior to MenPS for all four serogroups in adults, with significantly higher VR rates to serogroups A, W-135 and Y and an acceptable safety profile. Consistency of 3 ACWY-TT production lots was demonstrated. These data suggest that, if licensed, ACWY-TT conjugate vaccine may be used for protection against invasive meningococcal disease in healthy adults. This study is registered at clinicaltrials.gov NCT00453986
 
Reverse cumulative curves showing rSBA titers for N. meningitidis serogroups A, C, W-135 and Y. ACWY+F, Coad group; ACWY_F, ACWY-TT group; MenPS_F, MenPS group.
Co-administration of meningococcal serogroups A, C, W-135 and Y conjugate vaccine (ACWY-TT) with seasonal influenza vaccine was investigated in a subset of adults enrolled in a larger study evaluating lot-to-lot consistency of ACWY-TT and non-inferiority to licensed tetravalent meningococcal polysaccharide vaccine (MenPS). Subjects in this sub-study were randomized (3:1:1) to receive ACWY-TT alone (ACWY-TT group) or with seasonal influenza vaccine (Coad), or licensed MenPS alone. Serum bactericidal antibodies (rSBA) and serum haemagglutination-inhibition (HI) antibody titers were measured pre- and 1 mo post-vaccination. Non-inferiority of the Coad group compared with ACWY-TT group was demonstrated in terms of rSBA geometric mean antibody titers (GMTs) to serogroups A, W-135 and Y. For serogroup C the pre-defined non-inferiority limit was marginally exceeded. Post-vaccination rSBA GMTs were significantly higher (exploratory analysis) in the Coad group compared with the MenPS group for serogroups A, W-135, and Y and were similar to the MenPS group for serogroup C. Overall, > 97% of subjects achieved rSBA titers ≥ 1:128 for all serogroups. The Coad group met all criteria defined by the Committee on Human Medicinal Products (CHMP) for seroprotection, seroconversion and seroconversion factor for HI antibodies for all three influenza strains. Grade 3 solicited local/general symptoms were reported by ≤ 1.9% of subjects in any group. These data support the co-administration of ACWY-TT with seasonal influenza vaccine when protection is needed against both diseases. This study is registered at clinicaltrials.gov NCT00453986
 
Demographic characteristics of enrolled and vaccinated chil- dren (total vaccinated cohort) 
rsBa vaccine response rates at one month after administration of MenacWY-TT or MenacWY polysaccharide vaccine (aTp immunogenicity cohort) 
Incidence (with 95% cI) of solicited local and general symptoms occurring within 4 d after the first vaccination in children aged 2-5 y (A) or 6-10 y (B) (total vaccinated cohort). acWY-TT group, group of children who received one dose of MenacWYTT; Men-ps group, group of children who received one dose of the MenacWY polysaccharide vaccine. error bars represent 95% confidence intervals.
Incidence of meningococcal diseases is high in children, and effective vaccines are needed for this age group. In this phase II, open, controlled study, 309 children aged 2-10 y from Finland were randomized (3:1) into two parallel groups to receive one dose of meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY-TT group; n = 231) or a licensed meningococcal ACWY polysaccharide vaccine (Men-PS group; n = 78). Serum bactericidal activity using rabbit complement (rSBA) was evaluated up to three years post-vaccination. Exploratory comparisons suggested that rSBA vaccine response rates and geometric mean titers (GMTs) for each serogroup at one month post-vaccination and rSBA GMTs for serogroups A, W-135 and Y up to three years post-vaccination were higher in the ACWY-TT compared with Men-PS group, but did not detect any difference between groups in terms of rSBA-MenC GMTs at three years post-vaccination; this is explained by the higher proportion of children from the Men-PS group who were excluded because they were re-vaccinated with a monovalent meningococcal serogroup C vaccine due to loss of protective antibody levels against this serogroup. Although there was a higher incidence of local reactogenicity in the ACWY-TT group, general and unsolicited symptoms reporting rates were comparable in both groups. This study showed that MenACWY-TT was immunogenic with a clinically acceptable safety profile in children aged 2-10 y. MenACWY-TT induced higher functional antibody titers for all serogroups, which persisted longer for serogroups A, W-135 and Y, than the MenACWY polysaccharide vaccine. This study has been registered at www.clinicaltrials.gov NCT00427908.
 
The first prophylactic vaccine, Hecolin®, against hepatitis E virus (HEV) infection and the HEV associated disease was approved by China's State Food and Drug Administration (SFDA) in December 2011. Key milestones during the 14-year HEV vaccine development are summarized in this commentary. After years of innovative research the recombinant virus-like particle (VLP) based antigen with virion-like epitopes was successfully produced in E. coli production platform on a commercial scale. Safety and efficacy of this vaccine was demonstrated in a large scale phase III clinical trial.
 
Disposition of children. 1 JE neutralizing antibody titer 10 (1/dil) in children who were seronegative (titer < 10 [1/dil])at baseline or a 4-fold rise in JE neutralizing antibody titers in children who were seropositive (titer 10 [1/dil]) at baseline; 2 JE neutralizing antibody titer 10 (1/dil). 
A new live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) has been developed based on innovative technology to give protection against JE with an improved immunogenicity and safety profile. In this phase 3, observer-blind study, 274 children aged 12-24 months were randomized 1:1 to receive one dose of JE-CV (Group JE-CV) or the SA14-14-2 vaccine currently used to vaccinate against JE in the Republic of Korea (Group SA14-14-2). JE neutralizing antibody titers were assessed using PRNT50 before and 28 days after vaccination. The primary endpoint of non-inferiority of seroconversion rates on D28 was demonstrated in the Per Protocol analysis set as the difference between Group JE-CV and Group SA14-14-2 was 0.9 percentage points (95% confidence interval [CI]: -2.35; 4.68), which was above the required -10%. Seroconversion and seroprotection rates 28 days after administration of a single vaccine dose were 100% in Group JE-CV and 99.1% in Group SA14-14-2; all children except one (Group SA14-14-2) were seroprotected. Geometric mean titers (GMTs) increased in both groups from D0 to D28; GM of titer ratios were slightly higher in Group JE-CV (182 [95% CI: 131; 251]) than Group SA14-14-2 (116 [95% CI: 85.5, 157]). A single dose of JE-CV was well tolerated and no safety concerns were identified. In conclusion, a single dose of JE-CV or SA14-14-2 vaccine elicited a comparable immune response with a good safety profile. Results obtained in healthy Korean children aged 12-24 months vaccinated with JE-CV are consistent with those obtained in previous studies conducted with JE-CV in toddlers.
 
Vaccination is an effective means of preventing infectious diseases, including those caused by Helicobacter pylori. Th17 cell responses are critical for the pathogenesis of Helicobacter pylori infection. In view of Th17 responses to multi-epitope vaccine CTB-UE, the IL-17 production in antiserum was examined. CTB-UE decreased IL-17 production, implying that Th17 responses may be inhibited. Furthermore, IL-17 aggravated GES-1 cell injury induced by H. pylori SS1; In contrast, CTB-UE antiserum could evidently alleviate this cell injury, which suggesting that CTB-UE can protect GES-1 cell infected with H. pylori SS1 by inhibiting Th17 responses. Treatment of mice with CTB-UE significantly reduced the H. pylori burden and inflammation in the stomach. However, the production of IL-17 in the stomach in H. pylori-infected mice was increased; and the production of IL-17 was decreased after treatment with CTB-UE. Furthermore, the expression of microRNA-155 in gastric tissue was significantly up-regulated, implying that the microRNA-155/IL-17 pathway was involved. Further study is required to elucidate the relationship between miRNA-155 and IL-17. We found that the production of IL-17 was significantly increased after the expression of miRNA-155 being down-regulated; and the production of IL-17 was significantly decreased after the expression of miRNA-155 being up-regulated. The results suggested that CTB-UE could relieve the H. pylori-induced gastric inflammatory reaction via up-regulating microRNA-155 to inhibit Th17 responses.
 
study design (A) and flow of participants (B) throughout the study. a Women who received ≥1 dose of hPV-16/18 vaccine were invited for follow-up at month 24. b No women with high-grade cytology or missing cytology at baseline. c additional cytopathological examination could be performed per cytology management algorithm at month 42 if required. *Number of women eliminated from the analysis of the concerned cohort under the reason of "not participated in extended follow-up." The other women who did not participate in the extended follow-up study were eliminated with other reasons indicated in the same box. †Non-compliance with study procedure includes protocol violation, or randomization code broken, or noncompliance with the vaccine dose/schedule in the initial study, or administration of vaccine(s)/medication(s) forbidden by the protocol. abbreviations: aTP, according-to-protocol; hPV, hPV vaccine group; TVc, total vaccinated cohort; N, number of women; ae, adverse event. 
Number of cases of cIN1+ (A and C) and cIN2+ (B and D) associated with vaccine and non-vaccine hPV types in the TVc (A and B) and TVcnaïve (C and D) over the combined 4-y study period. Number of cases is shown inside the bars. Women included in the analysis of the TVc-naïve cohort were hPV DNa negative for all 14 oncogenic hPV types tested, seronegative for hPV-16 and hPV-18, and had negative cytology at baseline. Oncogenic hPV types tested were hPV-16,-18,-31,-33,-35,-39,-45,-51,-52,-56,-58,-59,-66 and-68. Follow-up period started on the day after the first vaccine dose. abbreviations: cIN1+, cervical intraepithelial neoplasia grade 1 or greater; cIN2+, cervical intraepithelial neoplasia grade 2 or greater; TVc, total vaccinated cohort.
anti-hPV-16 and anti-hPV-18 antibody GMTs from month 0 in initial study to month 48 in the present study (aTP kinetic cohort [N = 232 for hPV-16 and N = 233 for hPV-18]). The kinetics of the immune responses were evaluated in women from the aTP-I who were seronegative for the corresponding hPV type at baseline and had data available for each time point (aTP kinetic cohort). Long dashed lines: antibody titers at the plateau level (months 45-50) in a previous study in which sustained protection with the hPV-16/18 as04-adjuvanted vaccine was shown up to 6.4 y post-vaccination (i.e., 397.8 [344.7-459.1] eL.U/mL for hPV-16 and 297.3 [258.2-342.2] eL.U/mL for hPV-18). 21 short dashed lines: antibody titers in women (aged 15-25 y at time of enrolment) who were presumed to have cleared a natural infection prior to enrolment in a previous study (i.e., who were hPV DNa negative and seropositive at baseline for the hPV type analyzed; 29.8 [28.5-31.0] eL.U/mL for hPV-16 and 22.6 [21.6-23.6] eL.U/mL for hPV-18). 24 abbreviations: 95% cI, 95% confidence interval (lower limit-upper limit); eL.U, eLIsa units; GMT, geometric mean titer; M, month.
In this open, extended follow-up study (NCT00929526, Clinicaltrials.gov), we evaluated the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine efficacy, immunogenicity and safety up to 4 years after first vaccination in Japanese women aged 20-25 years. In the initial randomized, double-blind study (NCT00316693), 1040 women received the study vaccine or hepatitis A control vaccine; 752 women were included in the follow-up study. In women from the according-to-protocol efficacy cohort (ATP-E), who were initially seronegative for the HPV type analyzed, no cervical intraepithelial neoplasia (CIN) grade 1 or greater (CIN1+) cases associated with HPV-16/18 were reported in the HPV group, while in the control group, 5 cases were identified in extended follow-up analyses (vaccine efficacy [VE] 100% [95% CI: -3.7-100]) and 8 cases in combined initial and follow-up studies analyses (VE 100% [42.2-100]). In the ATP-E, VE against CIN1+ and CIN2+ associated with high-risk HPV types reached 66.4% (21.6-87.1) and 83.0% (22.1-98.2) in extended follow-up analyses, and 63.4% (28.8-82.3) and 77.3% (30.4-94.4) in analyses of combined studies, respectively. During the four-year period, protection against CIN1+ and CIN2+, irrespective of the HPV type, was 56.7% (32.8-72.6) and 54.9% (20.5-75.3) in women receiving ≥ 1 vaccine dose, regardless of baseline serostatus (total vaccinated cohort [TVC]) and 61.0% (11.8-84.2) and 73.9% (1.1-95.3) in women naïve to HPV infection at baseline (TVC-naïve), respectively. The high VE observed in Japanese women, accompanied by a sustained immune response and a clinically acceptable safety profile, support findings of large, international trials.
 
aes reported after each vaccination 
Laboratory parameters* 
An Escherichia coli-expressed recombinant bivalent human papillomavirus (types 16 and 18) vaccine candidate has been shown to be safe and immunogenic in preclinical trials. The safety of this vaccine was analyzed in an open-label phase I clinical trial in Jiangsu province, China. Thirty-eight healthy women from 18 to 55 y of age were enrolled and vaccinated at 0, 1, and 6 mo. Adverse events that occurred within 30 d after each injection and serious adverse events that occurred throughout the study were recorded. In addition, blood parameters were tested before and after each injection. All but one woman received all 3 doses. Thirty-two (84.2%) of the participants reported adverse events, all adverse events of which were mild, of short duration and resolved spontaneously. No serious adverse events occurred during the study. Changes in blood parameters after each injection were random, mild, and not clinically significant. These preliminary results show that a new Escherichia coli-expressed recombinant HPV 16/18 bivalent vaccine is well tolerated in healthy women and support further immunogenicity and efficacy studies for this HPV vaccine candidate.
 
This randomized, partially-blind study (ClinicalTrials.gov registration number NCT00541970) evaluated the immunogenicity and safety of 2-dose (2D) schedules of the HPV-16/18 AS04-adjuvanted vaccine. Results to Month (M) 24 have been reported previously and we now report data to M48 focusing on the licensed vaccine formulation (20 μg each of HPV-16 and -18 antigens) administered at M0,6 compared with the standard 3-dose (3D) schedule (M0,1,6). Healthy females (age stratified: 9-14, 15-19, 20-25 years) were randomized to receive 2D at M0,6 (n = 240) or 3D at M0,1,6 (n = 239). In the according-to-protocol immunogenicity cohort, all initially seronegative subjects seroconverted for HPV-16 and -18 antibodies and remained seropositive up to M48. For both HPV-16 and -18, geometric mean antibody titer (GMT) ratios (3D schedule in women aged 15-25 years divided by 2D schedule in girls aged 9-14 years) at M36 and M48 were close to 1, as they were at M7 when non-inferiority was demonstrated. The kinetics of HPV-16, -18, -31, and -45 antibody responses were similar for both groups and HPV-16 and -18 GMTs were substantially higher than natural infection titers. The vaccine had a clinically acceptable safety profile in both groups. In summary, antibody responses to a 2D M0,6 schedule of the licensed vaccine formulation in girls aged 9-14 years appeared comparable to the standard 3D schedule in women aged 15-25 years up to 4 years after first vaccination. A 2D schedule could facilitate implementation of HPV vaccination programs and improve vaccine coverage and series completion rates.
 
Vaccine efficacy against HPV-16/18 associated endpoints up to 8.4 y after first vaccination 
Prophylactic human papillomavirus (HPV) vaccines are now available and vaccination programs are being widely implemented, targeting adolescent girls prior to sexual debut. Since the risk of HPV exposure persists throughout a woman's sexual life, the duration of protection provided by vaccination is critical to the overall vaccine effectiveness. We report the long-term efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine (Cervarix (®) ) up to 8.4 y after the first vaccine dose. In an initial placebo-controlled study performed in US, Canada and Brazil, women aged 15-25 y with normal cervical cytology, HPV-16/18 seronegative by ELISA, DNA-negative for 14 oncogenic HPV types by PCR, received either the HPV-16/18 vaccine or placebo (n = 1,113). Subjects were followed up to 6.4 y after the first dose (n = 776). We report an additional 2-y follow-up for women enrolled from the Brazilian centers from the initial study (n = 436). During the current follow-up study (HPV-023, NCT00518336), no new infection or lesions associated with HPV-16/18 occurred in the vaccine group. Vaccine efficacy over the entire follow-up (up to 8.4 y) was 95.1% (84.6, 99.0) for incident infection, 100% (79.8, 100) for 6-mo persistent infection, 100% (56.1, 100) for 12-mo persistent infection and 100% (< 0, 100) for CIN2+ associated with HPV-16/18. All women in the vaccine group remained seropositive to both HPV-16/18, with antibody titers for total and neutralizing antibodies remaining several-folds above natural infection levels. The safety profile was clinically acceptable for both vaccine and control groups. This is, to date, the longest follow-up study for a licensed cervical cancer vaccine.
 
Demographic and baseline characteristics 
seropositivity rates and GMTs for anti-hPV-16 and -18 antibodies by age strata: vaccine group 
summary of safety and pregnancy outcomes
Immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine were evaluated in healthy Chinese females aged 9-45 years in 2 phase IIIB, randomized, controlled trials. Girls aged 9-17 years (ClinicalTrials.gov, NCT00996125) received vaccine (n = 374) or control (n = 376) and women aged 26-45 years (NCT01277042) received vaccine (n = 606) or control (n = 606) at months 0, 1, and 6. The primary objective was to show non-inferiority of anti-HPV-16 and -18 immune responses in initially seronegative subjects at month 7, compared with Chinese women aged 18-25 years enrolled in a separate phase II/III trial (NCT00779766). Secondary objectives were to describe the anti-HPV-16 and -18 immune response, reactogenicity and safety. At month 7, immune responses were non-inferior for girls (9-17 years) vs. young women (18-25 years): the upper limit of the 95% confidence interval (CI) for the geometric mean titer (GMT) ratio (women/girls) was below the limit of 2 for both anti-HPV-16 (0.37 [95% CI: 0.32, 0.43]) and anti-HPV-18 (0.42 [0.36, 0.49]). Immune responses at month 7 were also non-inferior for 26-45 year-old women vs. 18-25 year-old women: the upper limit of the 95% CI for the difference in seroconversion (18-25 minus 26-45) was below the limit of 5% for both anti-HPV-16 (0.00% [-1.53, 1.10]) and anti-HPV-18 (0.21% [-1.36, 1.68]). GMTs were 2- to 3-fold higher in girls (9-17 years) as compared with young women (18-25 years). The HPV-16/18 AS04-adjuvanted vaccine had an acceptable safety profile when administered to healthy Chinese females aged 9-45 years.
 
Vaccines have had a major role in enhancing the quality of life and increasing life expectancy. Despite these successes and the development of new vaccine technologies, there remain multiple infectious diseases including AIDS, malaria and tuberculosis that require effective prophylactic vaccines. New and traditional technologies have a role in the development and delivery of the new vaccine candidates. The scientific challenges, opportunities and funding models for developing vaccines for low resource settings are highlighted here.
 
Immunization is one of the most beneficial and cost-effective disease prevention measures. There are global efforts to develop new vaccines for disease control. The vaccine clinical trials must be conducted in the countries where they will be used. This has led to vaccine trials being conducted across Asia and Africa where there is a high burden of infectious diseases. The setup and successful conduct of International standard GCP vaccine trials across trial centers located in resource constrained settings are challenging. The challenges, ethical considerations and impact of the implementation of clinical trials in low-resource settings are highlighted here to help vaccine development programs successfully conduct such trials.
 
Human papillomavirus (HPV) vaccine uptake among 18-26 y old women varies by geographic region in the US. However, little is known about regional variations in vaccination among girls who are in the vaccine's targeted age groups. Regional variation in HPV vaccination among female adolescents (9-17 y old) was examined using cross-sectional data from the Behavioral Risk Factor Surveillance System (BRFSS) between 2008 and 2010. Multivariable logistic regression estimated the association of region of residence (10 states included questions about adolescent HPV vaccination) with uptake and completion of the 3-shot HPV vaccine series. Among 7,849 adolescents, 26.9% initiated, and 55.2% of initiators completed the series. Adolescents from Northeast/Midwest/West states were 1.74 (95% CI: 1.45-2.10) times more likely to have initiated HPV vaccination compared to the South/Southwestern states. Among initiators, vaccine series completion did not vary significantly between the South/Southwestern and Northeast/Midwest/West states. Flu vaccination was associated with increased odds of initiation in both regions and completion of the HPV vaccine series in the South/Southwestern states only. Girls 9-10 and 11-12 y old were less likely to have initiated and 11-12 y olds were less likely to have completed the HPV vaccine series compared to 13-17 y olds. The observed regional variations in vaccination could cause rates of cervical cancer to remain higher in the South/Southwest and widen currently observed regional disparities in cervical cancer rates.
 
The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following two alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016.
 
Abbey B Berenson a , Tabassum H Laz a , Jacqueline M Hirth a , Christine J McGrath a & Mahbubur  
The purpose of this study was to examine the relationship between human papillomavirus (HPV) vaccine uptake among adolescents aged 9-17 years and the decision-making process used by families in determining whether to vaccinate their children against HPV. A cross-sectional sample of women with at least one child aged 9-17 years (n = 1256) was recruited from 3 reproductive health clinics in Southeast Texas during 2011-2013. Self-administered survey included questions about the HPV vaccination decision-making process, HPV vaccine uptake (initiation and 3-dose series completion), and demographics. Among mothers with at least one 9-17-year-old daughter (n = 783), 40% independently decided whether or not to vaccinate their daughter against HPV, 22% involved their husbands/partners, and 31% their daughters. Only 7% of respondents reported other formats in the decision-making (husband/partner alone or daughter alone). Similarly, for women with at least one eligible son (n = 759), 39% decided alone, 30% with their husbands/partners, 24% with their sons, and 7% reported other formats. Among mothers with a daughter, those who made the decision independently were more likely to report that their daughters had initiated the HPV vaccine series (30%) compared with women who included their husbands/partners (10%) or daughters (20%) in the decision process or stated other types (18%) of decision making (P<0.001). The respective figures for the completion of the entire series among daughters were 16%, 6%, 11%, and 11% (P = 0.012). Among mothers with a son, a similar scenario was observed for vaccine initiation (17%, 4%, 10%, and 0%, respectively) (P<0.001) and completion (7%, 1%, 4%, and 0%, respectively) (P = 0.003). These associations remained significant after adjusting for confounder variables. Awareness programs to increase HPV vaccine uptake should include both parents and children, as all have an important role in deciding whether or not children will be vaccinated.
 
Despite the enormous efforts displayed globally in the fight against tuberculosis, the disease incidence has modified slightly, which has led to a renewed interest in immunotherapy. In general, successful immunotherapeutic candidates against tuberculosis are agents that can trigger strong, specific pro-inflammatory responses, especially of the T-helper (Th) 1 pattern. However, how these pro-inflammatory agents effectively kill the bacteria without eliciting immunopathology is not well understood. We reasoned that, in addition to the specific immune response elicited by immunotherapy, the evaluation of the overall pro-inflammatory responses should provide additional and valuable information that will be useful in avoiding immunopathology. We evaluated the overall IFN-γ and IL-17 pro-inflammatory responses among CD4 (+) , CD8 (+) and γδ T cells in the lungs of mice that were infected with M. tuberculosis and treated with a DNA vaccine in an immunotherapeutic regimen. Our results demonstrate that mice that effectively combat the pathogen develop a strong, specific Th1 immune response against the therapeutic antigen and have reduced lung inflammation, present in parallel a fine-tuning in the total IFN-γ- and IL-17-mediated immunity in the lungs. This modulation of the total immune response involves reducing the Th17 cell population, augmenting CD8 (+) T cells that produce IFN-γ and increasing the total γδ T cell frequency. These results stress the importance of a broad evaluation of not only the specific immune response at the time to evaluate new immune interventional strategies against tuberculosis but also non-conventional T cells, such as γδ T lymphocytes.
 
Interleukin-22 (IL-22) is mainly produced by activated Th1 cells, Th17 cells and NK cells and promotes anti-microbial defense, pro-inflammatory and tissue remodeling responses. However, its potential use as a vaccine adjuvant has not been tested. In this study, we tested if a DNA construct expressing IL-22 (pVAX-IL-22) could be used as a molecular adjuvant to enhance host immune responses induced by HBV DNA vaccination (pcD-S2). After immunizing mice with pcD-S2 combined with pVAX-IL-22, we didn't find enhancement of HBsAg-specific antibody responses in comparison to mice immunized with pcD-S2 alone. However, there was an enhancement of the level of IL-17 expression in antigen specific CD8 (+) cytotoxic T lymphocytes (Tc17). By using CD8 T-cell knockout (KO) and IL-17 KO mice, Tc17 cells were found to be a dominant population driving cytotoxicity. Importantly, there was a correlation between pVAX-IL-22 enhancement of T lymphocytes and a reduction of HBsAg-positive hepatocytes in HBsAg transgenic mice. These results demonstrate that IL-22 might be used as an effective adjuvant to enhance cellular immune responses during HBsAg DNA vaccination since it can induce Tc17 cells to break tolerance in HBsAg transgenic mice.
 
Baseline characteristics of children, according to age and study group
Vaccines were urgently needed in 2009 against A/H1N1 pandemic influenza. Based on the H5N1 experience, it was originally thought that 2 doses of an adjuvanted vaccine were needed for adequate immunogenicity. We tested H1N1 vaccines with or without AF03, a squalene-based adjuvant, in children. Two randomized, open-label, trials were conducted. Participants 3-17 y received two injections of 3.8 µg or 7.5 µg hemagglutinin (HA) with adjuvant or 15 µg HA without adjuvant. Participants aged 6-35 mo received two injections of 1.9 µg or 3.8 µg HA with full or half dose adjuvant or 7.5 µg HA without adjuvant. All subjects 3 to 17 y reached seroprotection (hemagglutination inhibition (HI) titer ≥ 40) after the first dose of the adjuvanted vaccine, and 94% and 98% in the 3-8 and 9-17 y groups respectively with the non-adjuvanted vaccine. In children aged 6-35 mo responses were modest after one dose, but after two doses virtually all children were seroprotected regardless of HA or adjuvant dose. In this age group, antibody titers were 5 to 7 times higher after adjuvanted than non-adjuvanted vaccine. The higher responses with the adjuvanted vaccine were also reflected as better antibody persistence. There was no clustering of adverse events that would be suggestive of a safety signal. While a single injection was sufficient in subjects from 3 y, in children aged 6-35 mo two injections of this A/H1N1 pandemic influenza vaccine were required. Formulation of this vaccine with adjuvant provided a significant advantage for immunogenicity in the latter age group.
 
On the 15-17th of May 2013, about 120 scientists, postdoctoral fellows and professors representing renowned academic institutes and senior scientists and executives from small biotechs, contract research organizations (CROs) and Big Pharma companies, gathered at the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland for the 4th international conference on Modern Vaccines and Adjuvants Formulation. Despite this relative small number, the speakers and attendees covered together a very broad field of expertise. Indeed, experts in microbiology, immunology, biochemistry, formulation, virus and nanoparticle characterization, vaccine production, quality control as well as regulatory professionals attended the conference and were able to present their works and discuss new developments within the field of vaccine and adjuvant development, characterization and approval process. This broad diversity was a highpoint of the conference and allowed for a stimulating environment and underlined the complexity of the challenges that the field currently faces in order to develop better or completely new vaccines and adjuvants.
 
expression of heterologous proteins at the e-NS1 expression site of YF17D virus 
The live-attenuated yellow fever 17D virus is one of the most outstanding human vaccines ever developed. It induces efficacious immune responses at a low production cost with a well-established manufacture process. These advantages make the YF17D virus attractive as a vector for the development of new vaccines. At the beginning of vector development, YF17D was genetically manipulated to express other flavivirus prM and E proteins, components of the viral envelope. While these 17D recombinants are based on the substitution of equivalent YF17D genes, other antigens from unrelated pathogens have also been successfully expressed and delivered by recombinant YF17D viruses employing alternative strategies for genetic manipulation of the YF17D genome. Herein, we discuss these strategies in terms of possibilities of single epitope or larger sequence expression and the main properties of these replication-competent viral platforms.
 
Top-cited authors
Eve Dube
  • Laval University
Paul Bramadat
  • University of Victoria
Real Roy
  • University of Victoria
Anne S De Groot
  • EpiVax, Inc. and University of Georgia
Roberto Gasparini
  • Università degli Studi di Genova