Background. Almost 700 cases of human infection with avian influenza A/H7N9 have been reported since 2013. Pandemic preparedness strategies include H7N9 vaccine development. Methods. We evaluated an ...inactivated H7N9 vaccine in an observer-blind study in healthy adults aged 18–64 years. Participants (420) were randomized to receive 1 of 4 AS03-adjuvanted vaccines (low or medium dose of hemagglutinin with AS03A or AS03B), one nonadjuvanted vaccine, or placebo. The coprimary immunogenicity objective determined whether adjuvanted vaccines elicited an immune response against the vaccine-homologous virus, 21 days after the second vaccine dose per US and European licensure criteria in the per-protocol cohort (n = 389). Results. All adjuvanted vaccines met regulatory acceptance criteria. In groups receiving adjuvanted formulations, seroconversion rates were ≥85.7%, seroprotection rates ≥91.1%, and geometric mean titers ≥92.9% versus 23.2%, 28.6%, and 17.2 for the nonadjuvanted vaccine. The AS03 adjuvant enhanced immune response at antigen-sparing doses. Injection site pain occurred more frequently with adjuvanted vaccines (in ≤98.3% of vaccinees) than with the nonadjuvanted vaccine (40.7%) or placebo (20.0%). None of the 20 serious adverse events reported were related to vaccination. Conclusions. Two doses of AS03-adjuvanted H7N9 vaccine were well tolerated and induced a robust antibody response at antigen-sparing doses in healthy adults. Clinical Trials Registration. NCT01999842.
Summary Background Rates of varicella have decreased substantially in countries implementing routine varicella vaccination. Immunisation is possible with monovalent varicella vaccine or a combined ...measles-mumps-rubella-varicella vaccine (MMRV). We assessed protection against varicella in naive children administered one dose of varicella vaccine or two doses of MMRV. Methods This study was done in ten European countries with endemic varicella. Healthy children aged 12–22 months were randomised (3:3:1 ratio, by computer-generated randomisation list, with block size seven) to receive 42 days apart (1) two doses of MMRV (MMRV group), or (2) MMR at dose one and monovalent varicella vaccine at dose two (MMR+V group), or (3) two doses of MMR (MMR group; control). Participants and their parents or guardians, individuals involved in assessment of any outcome, and sponsor staff involved in review or analysis of data were masked to treatment assignment. The primary efficacy endpoint was occurrence of confirmed varicella (by detection of varicella zoster virus DNA or epidemiological link) from 42 days after the second vaccine dose to the end of the first phase of the trial. Cases were graded for severity. Efficacy analyses were per protocol. Safety analyses included all participants who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov , number NCT00226499. Findings Between Sept 1, 2005, and May 10, 2006, 5803 children (mean age 14·2 months, SD 2·5) were vaccinated. In the efficacy cohort of 5285 children, the mean duration of follow-up in the MMRV group was 36 months (SD 8·8), in the MMR+V group was 36 months (8·5) and in the MMR group was 35 months (8·9). Varicella cases were confirmed for 37 participants in the MMRV group (two moderate to severe), 243 in the MMR+V group, and 201 in the MMR group. Second cases occurred for three participants (all in the MMR+V group). Varicella cases were moderate to severe for two participants in the MMRV group, 37 in the MMR+V group (one being a second case that followed a mild first case); and 117 in the MMR group. Efficacy of two-dose MMRV against all varicella was 94·9% (97·5% CI 92·4–96·6), and against moderate to severe varicella was 99·5% (97·5–99·9). Efficacy of one-dose varicella vaccine against all varicella was 65·4% (57·2–72·1), and against moderate to severe varicella (post hoc) was 90·7% (85·9–93·9). The most common adverse event in all groups was injection-site redness (up to 25% of participants). Within 15 days after dose one, 57·4% (95% CI 53·9–60·9) of participants in the MMRV group reported fever of 38°C or more, by contrast with 44·5% (41·0–48·1) with MMR+V, and 39·8% (33·8–46·1) with MMR. Eight serious adverse events were deemed related to vaccination (three MMRV, four MMR+V, one MMR). All resolved within the study period. Interpretation These results support the implementation of two-dose varicella vaccination on a short course, to ensure optimum protection from all forms of varicella disease. Funding GlaxoSmithKline Vaccines.
Immunization against Hepatitis E Innis, Bruce L; Lynch, Julia A
Cold Spring Harbor perspectives in medicine,
11/2018, Letnik:
8, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Soon after the 1991 molecular cloning of hepatitis E virus (HEV), recombinant viral capsid antigens were expressed and tested in nonhuman primates for protection against liver disease and infection. ...Two genotype 1 subunit vaccine candidates entered clinical development: a 56 kDA vaccine expressed in insect cells and HEV 239 vaccine expressed in
Both were highly protective against hepatitis E and acceptably safe. The HEV 239 vaccine was approved in China in 2011, but it is not yet prequalified by the World Health Organization, a necessary step for introduction into those low- and middle-income countries where the disease burden is highest. Nevertheless, the stage is set for the final act in the hepatitis E vaccine story-policymaking, advocacy, and pilot introduction of vaccine in at-risk populations, in which it is expected to be cost-effective.
A successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine must not only be safe and protective, but must also meet the demand on a global scale at a low cost. Using the ...current influenza virus vaccine production capacity to manufacture an egg-based inactivated Newcastle disease virus (NDV)/SARS-CoV-2 vaccine would meet that challenge. Here, we report pre-clinical evaluations of an inactivated NDV chimera stably expressing the membrane-anchored form of the spike (NDV-S) as a potent coronavirus disease 2019 (COVID-19) vaccine in mice and hamsters. The inactivated NDV-S vaccine was immunogenic, inducing strong binding and/or neutralizing antibodies in both animal models. More importantly, the inactivated NDV-S vaccine protected animals from SARS-CoV-2 infections. In the presence of an adjuvant, antigen-sparing could be achieved, which would further reduce the cost while maintaining the protective efficacy of the vaccine.
An affordable pneumococcal conjugate vaccine (PCV) is needed to ensure sustainable access in low-income and middle-income countries. This trial examined the immunogenicity and safety of a novel ...ten-valent PCV (SIIPL-PCV) containing serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, and 23F compared with the pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV; Synflorix; GlaxoSmithKline; Brentford, UK).
In this single-centre, randomised, double-blind, phase 3, non-inferiority trial in The Gambia, healthy, PCV-naive infants aged 6–8 weeks were enrolled and assigned using permuted block randomisation to receive one of three lots of SIIPL-PCV or to PHiD-CV in a ratio of 2:2:2:3. Parents and all staff assessing study outcomes were masked to group assignment. Vaccines (0·5 mL SIIPL-PCV or 0·5 mL PHiD-CV) were administered at ages 6, 10, and 14 weeks by intramuscular injection. Primary immunogenicity outcomes, measured at age 18 weeks, were serotype-specific IgG geometric mean concentrations (GMCs) and seroresponse rates (IgG ≥ 0·35 μg/mL). Lot-to-lot equivalence (objective 1) was shown if the upper and lower bounds of the two-sided 95% CI around the GMC ratio for each pairwise lot-to-lot comparison was between the 0·5 and 2·0 equivalence margins for all ten serotypes. The immunogenicity of SIIPL-PCV was defined as being non-inferior to that of PHiD-CV (objective 2) if, for at least seven of the ten serotypes in SIIPL-PCV, the lower bound of the 97·5% CI for the GMC ratio was greater than 0·5, or the lower bound of the 97·5% CI for differences in seroresponse rate was greater than −10%. The GMC and seroresponse rates to serotypes 6A and 19A, which are not in PHiD-CV, were compared with those of the serotype in PHiD-CV that had the lowest seroresponse rate. Non-inferiority of the immune responses to antigens in the co-administered Expanded Programme on Immunization (EPI) vaccines (objective 3) was declared if the lower bound of the 95% CI for the difference between SIIPL-PCV and PHiD-CV in seroresponse rates, or GMC ratios for pertussis antigens, was greater than −10% (or 0·5 for pertussis antigens) for all vaccine antigens. Safety data were assessed according to treatment received at the first visit in infants who received at least one dose of study vaccine and for whom at least some post-vaccination safety data were available. The primary immunogenicity analysis was in the per-protocol immunogenicity population, which included infants who received all study vaccines and had immunogenicity measurements after vaccination and no major protocol deviations. This trial is registered at ClinicalTrials.gov (NCT03197376).
Between June 21, 2017, and Jan 29, 2018, 2250 infants were enrolled and randomly assigned to receive SIIPL-PCV (n=1503; 502 to lot 1, 501 to lot 2, and 500 to lot 3) or PHiD-CV (n=747). 1458 (97·0%) infants assigned to SIIPL-PCV and 724 (96·9%) assigned to PHiD-CV were included in the per-protocol primary immunogenicity analysis. Lot-to-lot equivalence was shown, with the lowest lower bound of the 95% CI for the GMC ratio being 0·52 (for serotype 6B in lot 2 vs lot 3) and the highest upper bound being 1·69 (for serotype 6B in lot 1 vs lot 2). SIIPL-PCV was non-inferior to PHiD-CV in terms of immunogenicity: the lower bound of the 97·5% CI for the GMC ratio was greater than 0·5 (the lowest being 0·67 for serotype 19F) and the lower bound of the 97·5% CI for the difference in seroresponse rate was greater than −10% (the lowest being −2·2% for serotype 6B) for all ten serotypes in SIIPL-PCV. The lowest seroresponse rate after PHiD-CV was to serotype 6B (76·7% 95% CI 73·4–79·7). This serotype was therefore used for the comparisons with serotype 6A and 19A in SIIPL-PCV. Non-inferiority of immune responses to the EPI vaccines after co-administration with SIIPL-PCV compared with after co-administration with PHiD-CV was shown for all vaccine antigens included in the primary series. The lowest lower bound of the 95% CI for the difference in seroresponse rates was −7·1% for rotavirus antibody and for the GMC ratio for pertussis antigens was 0·62 for anti-pertussis toxoid. 1131 (75·2%) of 1503 infants in the SIIPL-PCV group and 572 (76·6%) of 747 in the PHiD-CV group had at least one unsolicited adverse event. 36 (2·4%) participants in the SIIPL-PCV group and 18 (2·4%) in the PHiD-CV group had a serious adverse event; none were considered related to vaccination. In infants who were selected to have solicited adverse events recorded, injection-site induration after primary vaccinations occurred in 27 (4·9%) of 751 infants who received SIIPL-PCV versus 34 (9·4%) of 364 who received PHiD-CV (p=0·0032). There were no other notable differences in the safety profiles of the two vaccines. One infant in the SIIPL-PCV group and two in the PHiD-CV group died during the study. The deaths were not considered to be related to study vaccination or study participation.
The immunogenicity of SIIPL-PCV was non-inferior to that of PHiD-CV, for which efficacy and effectiveness data against pneumococcal disease are available. The vaccine is safe and can be co-administered with routine EPI vaccines. The data generated in this trial have supported the licensure and pre-qualification of SIIPL-PCV, making the vaccine available for introduction into national immunisation programmes. Generating post-implementation data confirming vaccine impact remains important.
Bill & Melinda Gates Foundation.
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) and hospitalization in infants and children globally. Many observational studies have found an ...association between RSV LRTI in early life and subsequent respiratory morbidity, including recurrent wheeze of early childhood (RWEC) and asthma. Conversely, two randomized placebo-controlled trials of efficacious anti-RSV monoclonal antibodies (mAbs) in heterogenous infant populations found no difference in physician-diagnosed RWEC or asthma by treatment group. If a causal association exists and RSV vaccines and mAbs can prevent a substantial fraction of RWEC/asthma, the full public health value of these interventions would markedly increase. The primary alternative interpretation of the observational data is that RSV LRTI in early life is a marker of an underlying predisposition for the development of RWEC and asthma. If this is the case, RSV vaccines and mAbs would not necessarily be expected to impact these outcomes. To evaluate whether the available evidence supports a causal association between RSV LRTI and RWEC/asthma and to provide guidance for future studies, the World Health Organization convened a meeting of subject matter experts on February 12–13, 2019 in Geneva, Switzerland. After discussing relevant background information and reviewing the current epidemiologic evidence, the group determined that: (i) the evidence is inconclusive in establishing a causal association between RSV LRTI and RWEC/asthma, (ii) the evidence does not establish that RSV mAbs (and, by extension, future vaccines) will have a substantial effect on these outcomes and (iii) regardless of the association with long-term childhood respiratory morbidity, severe acute RSV disease in young children poses a substantial public health burden and should continue to be the primary consideration for policy-setting bodies deliberating on RSV vaccine and mAb recommendations. Nonetheless, the group recognized the public health importance of resolving this question and suggested good practice guidelines for future studies.
•Without immune correlates, dengue vaccine efficacy trials require clinical endpoints.•Recent evidence impacts trial design and follow-up of 2nd generation dengue vaccines.•Vaccine safety and ...efficacy stratified by pre-vaccination serostatus is essential.•Trial data should be interpreted with consideration of transient heterotypic immunity.
Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines.
•Recombinant pertussis vaccine is safe for both mother and newborn.•There is effective transplacental antibody transfer to infants at birth.•No difference in antibody response is shown during 2nd or ...3rd trimester of pregnancy.
Recombinant acellular pertussis (ap) vaccines containing genetically inactivated pertussis toxin (PTgen) and filamentous hemagglutinin (FHA) with or without tetanus (TT) and diphtheria (DT) vaccines (Td) were found safe and immunogenic in non-pregnant and pregnant women. We report here maternal antibody transfer and safety data in mothers and neonates.
This is the follow up of a phase 2 trial in 2019 among 400 pregnant women who randomly received one dose of recombinant pertussis-only vaccine containing 1 µg PTgen and 1 µg FHA (ap1gen), or Td combined with ap1gen (Tdap1gen), or with 2 µg PTgen and 5 µg FHA (Tdap2gen), or with 5 µg PTgen and 5 µg FHA (TdaP5gen, Boostagen®, BioNet, Thailand) or chemically-inactivated acellular pertussis comparator (Tdap8chem, Boostrix™, GSK, Belgium), either in the second or third trimester of gestation. IgG against PT, FHA, TT and DT were assessed by ELISA, PT-neutralizing antibodies (PTNA) by Chinese Hamster Ovary cell assay and safety outcomes at delivery in mothers and at birth.
Anti-PT and anti-FHA geometric mean concentration (GMC) ratio between infants at birth and mothers at delivery was above 1 in all groups. PT GMC in infants at birth were ≥30 IU/mL in all groups with the highest titers in infants found in TdaP5gen group at birth (118.8 95% CI 93.9–150.4). At 2 months, PT GMC ratio to Tdap8chem (98.75% CI) was significantly higher for TdaP5gen (2.6 1.7–4.0) and comparable for other recombinant vaccines. No difference in PTNA titers at birth was observed between all groups nor between time of vaccination. Adverse events were comparable in all vaccine groups.
BioNet licensed (TdaP5gen and Tdap2gen) and candidate vaccines (Tdap1gen and ap1gen) when given to pregnant women in the second or third trimester of gestation are safe and have induced passive pertussis immunity to infants.
Two antigenically distinct influenza B lineages have co-circulated since the 1980s, yet inactivated trivalent influenza vaccines (TIVs) include strains of influenza A/H1N1, A/H3N2, and only one ...influenza B from either the Victoria or Yamagata lineage. This means that exposure to B-lineage viruses mismatched to the TIV is frequent, reducing vaccine protection. Formulations including both influenza B lineages could improve protection against circulating influenza B viruses. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages versus TIV in adults in stable health.
A total of 4659 adults were randomized 5:5:5:5:3 to receive one dose of QIV (one of three lots) or a TIV containing either a B/Victoria or B/Yamagata strain. Hemagglutination-inhibition assays were performed pre-vaccination and 21-days after vaccination. Lot-to-lot consistency of QIV was assessed based on geometric mean titers (GMT). For QIV versus TIV, non-inferiority against the three shared strains was demonstrated if the 95% confidence interval (CI) upper limit for the GMT ratio was ≤1.5 and for the seroconversion difference was ≤10.0%; superiority of QIV versus TIV for the alternate B lineage was demonstrated if the 95% CI lower limit for the GMT ratio was > 1.0 and for the seroconversion difference was > 0%. Reactogenicity and safety profile of each vaccine were assessed. Clinicaltrials.gov: NCT01204671.
Consistent immunogenicity was demonstrated for the three QIV lots. QIV was non-inferior to TIV for the shared vaccine strains, and was superior for the added alternate-lineage B strains. QIV elicited robust immune responses against all four vaccine strains; the seroconversion rates were 77.5% (A/H1N1), 71.5% (A/H3N2), 58.1% (B/Victoria), and 61.7% (B/Yamagata). The reactogenicity and safety profile of QIV was consistent with TIV.
QIV provided superior immunogenicity for the additional B strain compared with TIV, without interfering with antibody responses to the three shared antigens. The additional antigen did not appear to alter the safety profile of QIV compared with TIV. This suggests that the candidate QIV is a viable alternative to TIV for use in adults, and could potentially improve protection against influenza B.
Clinical Trials.gov: NCT01204671/114269.
Summary Background We aimed to compare AS03-adjuvanted inactivated trivalent influenza vaccine (TIV) with non-adjuvanted TIV for seasonal influenza prevention in elderly people. Methods We did a ...randomised trial in 15 countries worldwide during the 2008–09 (year 1) and 2009–10 (year 2) influenza seasons. Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were randomly assigned (1:1) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV. Randomisation was done in an internet-based system, with a blocking scheme and stratification by age (65–74 years and 75 years or older). Participants were scheduled to receive one vaccine in each year, and remained in the same group in years 1 and 2. Unmasked personnel prepared and gave the vaccines, but participants and individuals assessing any study endpoint were masked. The coprimary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV (to be reported elsewhere). For the first objective, the primary endpoint was relative efficacy of the vaccines for prevention of influenza A (excluding A H1N1 pdm09) or B, or both, that was confirmed by PCR analysis in year 1 (lower limit of two-sided 95% CI had to be greater than zero to establish superiority). From Nov 15, to April 30, in both years, participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness. After onset of suspected cases, we obtained nasal and throat swabs to identify influenza RNA with real-time PCR. Efficacy analyses were done per protocol. This trial is registered with ClinicalTrials.gov , number NCT00753272. Findings We enrolled 43 802 participants, of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1. In the year 1 efficacy cohort, fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B, or both (274 1·27%, 95% CI 1·12–1·43 of 21 573 vs 310 1·44%, 1·29–1·61 of 21 482; relative efficacy 12·11%, 95% CI −3·40 to 25·29; superiority not established). Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A (224 1·04%, 95% CI 0·91–1·18 vs 270 1·26, 1·11–1·41; relative efficacy 17·53%, 95% CI 1·55–30·92) and influenza A H3N2 (170 0·79, 0·67–0·92 vs 205 0·95, 0·83–1·09; post-hoc analysis relative efficacy 22·0%, 95% CI 5·68–35·49). Interpretation AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV. Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints. Funding GlaxoSmithKline Biologicals SA.
PDF
