Safety and immunogenicity of Sinovac's prototype pandemic influenza H5N1 vaccines: a review on clinical trials.
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ABSTRACT:
SUBMITTER: Qiu YZ
PROVIDER: S-EPMC4634113 | biostudies-other | 2008 Nov
REPOSITORIES: biostudies-other
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Project description:Our studies aimed to evaluate in clinical trials the safety and immunogenicity of an H5 live influenza vaccine candidate obtained using classical reassortment techniques from a low pathogenicity avian influenza (LPAI) A/Duck/Potsdam/1402-6/86(H5N2) virus and the cold-adapted (ca) donor strain A/Leningrad/134/17/57(H2N2).During Phase I-II clinical trials, volunteers received intranasally two doses of reassortant influenza vaccine strain A/17/Duck/Potsdam/86/92 (H5N2) 21 days apart. Clinical examination of all vaccinees was conducted 7 days post-vaccination. Serum antibody responses were measured by hemagglutination-inhibition and microneutralization and local antibodies were estimated using an enzyme-linked immunosorbent assay test.The vaccine was safe and of low reactogenicity with no febrile reactions. After revaccination 47.1-54.8% of subjects showed > or =fourfold seroconversions of Hamagglutination inhibition (HAI) antibodies to the hemagglutinin (HA) antigen of the A/17/Duck/Potsdam/86/92 (H5N2) virus and 29.4-30.8% were seroconverted to the HA antigen of the reverse genetics reassortant A/Indonesia/05/2005 x PR8 IBCDC-RG (H5N1). Virus-neutralizing antibody levels in sera of volunteers were similar to those shown in HAI test. The virus-specific nasal IgA antibody response after two vaccine doses demonstrated significant increases of > or =fourfold rise SIgA antibodies (65%) geometrical mean titers (16.0) and a rise in SIgA antibodies (2.8) compared with one dose.The live attenuated influenza vaccine candidate prepared using the LPAI A(H5N2) strain was well tolerated and elicited serum and local immune responses. There was evident cross-reactivity to the A(H5N1) strain in the HAI test.
| S-EPMC4634119 | biostudies-other
Project description:BackgroundA/H5N1 influenza viruses have high pandemic potential; consequently, vaccines need to be produced rapidly. MF59® adjuvant reduces the antigen required per dose, allowing for dose sparing and more rapid vaccine availability.MethodsTwo multicenter, phase II trials were conducted to evaluate the safety and immunogenicity of an MF59-adjuvanted, cell culture-derived, A/H5N1 vaccine (aH5N1c) among 979 adult (18-64 years old) and 1393 elderly (≥65 years old) subjects. Participants were equally randomized to receive 2 full-dose (7.5 μg of hemagglutinin antigen per dose) or 2 half-dose aH5N1c vaccinations 3 weeks apart. Outcomes were based on Center for Biologics Evaluation Research and Review (CBER) and Committee for Medicinal Products for Human Use (CHMP) licensure criteria (titers ≥1:40 and seroconversions on day 43). Solicited reactions and adverse events were assessed (www.clinicaltrials.gov: NCT01776541 and NCT01766921).ResultsCBER and CHMP criteria were met by both age groups. CBER criteria for hemagglutination titers were met for the full-dose formulation. Solicited reaction frequencies tended to be higher in the full-dose group and were of mild to moderate intensity. No vaccine-related serious adverse events occurred.ConclusionsIn adult and elderly participants, the full-dose aH5N1c vaccine formulation was well tolerated and met US and European licensure criteria for pandemic vaccines.
| S-EPMC6446137 | biostudies-literature
Project description:Influenza vaccine production capacity is still insufficient to meet global demand in case of a pandemic. To expand worldwide influenza vaccine production capacity, a solid and transferable egg-based influenza vaccine production process was established that is suitable for upscaling and technology transfer to vaccine manufacturers in low- and middle-income countries. As a proof-of-concept, the safety and immunogenicity of a pandemic whole inactivated virus (WIV) vaccine (H5N1) and a monovalent seasonal WIV vaccine (H3N2) were evaluated in a phase I clinical trial in adults.Subjects were vaccinated with 2 doses of pandemic WIV vaccine (pWIV), or one dose of either seasonal WIV vaccine (sWIV) or a commercially available trivalent comparator vaccine followed by a placebo dose. Haemagglutination inhibiting antibody titres against the influenza strains were determined before and 21 d after each vaccination.The frequency and severity of adverse reactions were comparable between groups. No serious adverse events were reported. After a single dose of sWIV the seroconversion rate was 91% (Committee for Proprietary Medicinal Products (CPMP) criterion >40%), the seroprotection rate was 100% (CPMP criterion >70%), and the mean geometric mean titre (GMT) increase was 24.9 (CPMP criterion >2.5). After two doses of pWIV, seroconversion rate and seroprotection rate were both 71%, and the mean GMT increase was 7.8.Both pWIV and sWIV were equally well-tolerated as the comparator vaccine, and both vaccines complied with all 3 CPMP criteria. EudraCT 2011-000159-17. Netherlands National Trial Register 2695.
| S-EPMC4514258 | biostudies-literature
Project description:Clinical trials have shown that AS03-adjuvanted H5N1 and A(H1N1)pdm09 vaccines are highly immunogenic, although with an increased reactogenicity profile relative to non-adjuvanted vaccines in terms of the incidence of common injection site and systemic adverse events (AEs). We evaluated pooled safety data from 22,521 adults who had received an AS03-adjuvanted H5N1 or A(H1N1)pdm09 influenza or control vaccine with the purpose to identify medically-attended AEs (MAEs), including subsets of serious AEs (SAEs), potentially immune-mediated diseases (pIMDs), and AEs of special interest (AESI), and to explore a potential association of these AEs with the administration of an AS03-adjuvanted influenza vaccine. For participants who had received an AS03-adjuvanted vaccine, the relative risks (RRs) for experiencing a MAE or a SAE compared to control group (participants who had received a non-adjuvanted vaccine or saline placebo) were 1.0 (95% confidence interval [CI]: 0.9; 1.1) and 1.1 (95% CI: 0.9; 1.4), respectively. The overall RRs for experiencing an AESI or a pIMD (AS03-adjuvanted vaccine/control) were 1.2 (95% CI: 0.9; 1.6) and 1.7 (95% CI: 0.8; 3.8), respectively. Thirty-8 participants in the AS03-adjuvanted vaccine group had a pIMD reported after vaccine administration, yielding an incidence rate (IR) of 351.9 (95% CI: 249.1; 483.1) per 100,000 person-years. The estimated IRs in the AS03-adjuvanted vaccine group were greater than the literature reported rates for: facial paresis/VIIth nerve paralysis, celiac disease, thrombocytopenia and ulcerative colitis. These results do not support an association between AS03-adjuvanted H5N1 and A(H1N1)pdm09 vaccines and the AEs collected in the trials included in the analysis.
| S-EPMC5443104 | biostudies-literature
Project description:More than 15 years after the first human cases of influenza A/H5N1 in Hong Kong, the world remains at risk for an H5N1 pandemic. Preparedness activities have focused on antiviral stockpiling and distribution, development of a human H5N1 vaccine, operationalizing screening and social distancing policies, and other non-pharmaceutical interventions. The planning of these interventions has been done in an attempt to lessen the cumulative mortality resulting from a hypothetical H5N1 pandemic. In this theoretical study, we consider the natural limitations on an H5N1 pandemic's mortality imposed by the virus' epidemiological-evolutionary constraints. Evolutionary theory dictates that pathogens should evolve to be relatively benign, depending on the magnitude of the correlation between a pathogen's virulence and its transmissibility. Because the case fatality of H5N1 infections in humans is currently 60 per cent, it is doubtful that the current viruses are close to their evolutionary optimum for transmission among humans. To describe the dynamics of virulence evolution during an H5N1 pandemic, we build a mathematical model based on the patterns of clinical progression in past H5N1 cases. Using both a deterministic model and a stochastic individual-based simulation, we describe (i) the drivers of evolutionary dynamics during an H5N1 pandemic, (ii) the range of case fatalities for which H5N1 viruses can successfully cause outbreaks in humans, and (iii) the effects of different kinds of social distancing on virulence evolution. We discuss two main epidemiological-evolutionary features of this system (i) the delaying or slowing of an epidemic which results in a majority of hosts experiencing an attenuated virulence phenotype and (ii) the strong evolutionary pressure for lower virulence experienced by the virus during a period of intense social distancing.
| S-EPMC3675429 | biostudies-other
Project description:BACKGROUND:A key consideration for expanding recommendations for influenza vaccination is a robust assessment of immunogenicity and efficiency of transplacental antibody transfer after maternal vaccination. METHODS:We pooled data from two trials of maternal influenza vaccination to analyze vaccine immunogenicity with more power than either trial had alone. We compared hemagglutination-inhibition (HAI) titers and titer factor change for women and their infants between trial arms using t-tests; maternal and infant putative seroprotective titers (HAI ? 1:40) within each trial arm and maternal seroconversion between trial arms using exact tests; and transplacental antibody transfer between trial arms using t-tests. We used marginal linear models and generalized estimating equations to examine the impact of time between maternal vaccination and delivery on transplacental antibody transfer, infant titers, and infant seroprotection. RESULTS:For all vaccine components (A/H1N1, A/H3N2, and Type B), >80% of vaccinated women had seroprotective titers, >60% of them seroconverted, and >50% of their infants were born with seroprotective titers. These immunogenicity outcomes occurred more often in vaccine recipients and their infants than in controls. No difference in efficiency of transplacental antibody transfer was observed between vaccine recipients and controls. CONCLUSIONS:Our results provide robust support for further expansion of maternal influenza vaccination recommendations. CLINICAL TRIALS REGISTRATION:NCT01430689 and NCT01306669.
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Project description:Challenges facing seasonal and pandemic influenza vaccination include: increasing the immunogenicity of seasonal vaccines for the most vulnerable, increasing vaccination coverage against seasonal influenza, and developing vaccines against pandemic strains that are immunogenic with very low quantities of antigen to maximize the number of people who can be vaccinated with a finite production capacity. We review Sanofi Pasteur's epidemic and pandemic influenza research and development programmes with emphasis on two key projects: intradermal influenza vaccine for seasonal vaccination of both elderly and younger adults, and pandemic influenza vaccine.
| S-EPMC4634120 | biostudies-other
Project description:The emergence of the 2009 H1N1 pandemic has highlighted the need to have immunogenicity and safety data on the new pandemic vaccines. There is already considerable heterogeneity in the types of vaccine available and of study performed around the world. A systematic review and meta-analysis is needed to assess the immunogenicity and safety of pandemic influenza A (H1N1) 2009 vaccines. We searched Medline, EMBASE, the Cochrane Library and other online databases up to 1st October 2010 for studies in any language comparing different pandemic H1N1 vaccines, with or without placebo, in healthy populations aged at least 6 months. The primary outcome was seroprotection according to haemagglutination inhibition (HI). Safety outcomes were adverse events. Meta-analysis was performed for the primary outcome. We identified 18 articles, 1 only on safety and 17 on immunogenicity, although 1 was a duplicate. We included 16 articles in the meta-analysis, covering 17,921 subjects. Adequate seroprotection (?70%) was almost invariably achieved in all age groups, and even after one dose and at low antigen content (except in children under 3 years receiving one dose of non-adjuvanted vaccine). Non-adjuvanted vaccine from international companies and adjuvanted vaccines containing oil in water emulsion (e.g. AS03, MF59), rather than aluminium, performed better. Two serious vaccination-associated adverse events were reported, both of which resolved fully. No death or case of Guillain-Barré syndrome was reported. The pandemic influenza (H1N1) 2009 vaccine, with or without adjuvant, appears generally to be seroprotective after just one dose and safe among healthy populations aged ?36 months; very young children (6-35 months) may need to receive two doses of non-adjuvanted vaccine or one dose of AS03(A/B)-adjuvanted product to achieve seroprotection.
| S-EPMC4986623 | biostudies-literature
Project description:ImportanceLow-dose intradermal influenza vaccines could be a suitable alternative to full intramuscular dose during vaccine shortages.ObjectiveTo compare the immunogenicity and safety of the influenza vaccine at reduced or full intradermal doses with full intramuscular doses to inform policy design in the event of vaccine shortages.Data sourcesMEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from 2010 until June 5, 2020.Study selectionAll comparative studies across all ages assessing the immunogenicity or safety of intradermal and intramuscular influenza vaccinations were included.Data extraction and synthesisData were extracted by a single reviewer and verified by a second reviewer. Discrepancies between reviewers were resolved through consensus. Random-effects meta-analysis was conducted.Main outcomes and measuresPrimary outcomes included geometric mean titer, seroconversion, seroprotection, and adverse events.ResultsA total of 30 relevant studies were included; 29 studies were randomized clinical trials with 13 759 total participants, and 1 study was a cohort study of 164 021 participants. There was no statistically significant difference in seroconversion rates between the 3-µg, 6-µg, 7.5-µg, and 9-µg intradermal vaccine doses and the 15-µg intramuscular vaccine dose for each of the H1N1, H3N2, and B strains, but rates were significantly higher with the 15-µg intradermal dose compared with the 15-µg intramuscular dose for the H1N1 strain (rate ratio [RR], 1.10; 95% CI, 1.01-1.20) and B strain (RR, 1.40; 95% CI, 1.13-1.73). Seroprotection rates for the 9-µg and 15-µg intradermal doses did not vary significantly compared with the 15-µg intramuscular dose for all the 3 strains, except for the 15-µg intradermal dose for the H1N1 strain, for which rates were significantly higher (RR, 1.05; 95% CI, 1.01-1.09). Local adverse events were significantly higher with intradermal doses than with the 15-µg intramuscular dose, particularly erythema (3-µg dose: RR, 9.62; 95% CI, 1.07-86.56; 6-µg dose: RR, 23.79; 95% CI, 14.42-39.23; 9-µg dose: RR, 4.56; 95% CI, 3.05-6.82; 15-µg dose: RR, 3.68; 95% CI, 3.19-4.25) and swelling (3-µg dose: RR, 20.16; 95% CI, 4.68-86.82; 9-µg dose: RR, 5.23; 95% CI, 3.58-7.62; 15-µg dose: RR, 3.47 ; 95% CI, 2.21-5.45). Fever and chills were significantly more common with the 9-µg intradermal dose than the 15-µg intramuscular dose (fever: RR, 1.36; 95% CI, 1.03-1.80; chills: RR, 1.24; 95% CI, 1.03-1.50) while all other systemic adverse events were not statistically significant for all other doses.Conclusions and relevanceThese findings suggest that reduced-dose intradermal influenza vaccination could be a reasonable alternative to standard dose intramuscular vaccination.
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Project description:Considering the pandemic potential of avian influenza A/H5N1, development of an effective and well-tolerated vaccine is an essential part of pandemic preparedness plans. This phase III, randomized, double-blind study was conducted to assess the immunogenicity and safety profile of an alum-adjuvanted, whole virion, pre-pandemic influenza A/H5N1 vaccine (MG1109). Healthy individuals were randomly assigned, in a 3:1 ratio, to receive two doses of either MG1109 or placebo containing alum gel. Immunogenicity was determined by hemagglutination inhibition (HI) and microneutralization (MN) assays. Solicited and unsolicited adverse events were assessed after vaccination. Among 420 enrolled subjects, 418 were available for safety analysis, and 298 MG1109 recipients were available for per-protocol immunogenicity analyses. According to the HI assays, after two vaccine doses, all three of the Committee for Medicinal Products for Human Use (CHMP) criteria were met against the vaccine strain for all age groups: seroprotection rate = 74.8% (95% CI: 69.9 - 79.8), seroconversion rate = 67.8% (95% CI: 62.5-73.1), and geometric mean titer ratio (GMTR) = 5.9 (95% CI: 5.4 - 6.4). According to the MN assays, the GMTR was 2.4 (95% CI: 2.1 - 2.7) and 7.0 (95% CI: 6.3 - 7.9) three weeks after the first and second vaccine doses, respectively. Solicited local and systemic adverse events were mostly mild to moderate and were not significantly different between MG1109 and placebo recipients. In conclusion, two-dose administration of alum-adjuvanted H5N1 pre-pandemic influenza vaccine (MG1109) was highly immunogenic and tolerable in adults.
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