For the first time in history, the conditions to influence the course of an influenza pandemic through vaccination were set during the influenza A H1N1 pandemic in 2009. The specific requirements for pandemic vaccines are to be highly immunogenic in immunologically naive individuals and to be producible quickly in large quantities. In contrast, seasonal influenza vaccines induce a booster response and a broadening of preexisting immunity. In this article the concepts of seasonal and pandemic influenza vaccines and data on their immunogenicity and clinical efficacy are reviewed and discussed. In the upcoming years, seasonal influenza vaccination will continue to be based on inactivated split-virion and subunit vaccines or the live attenuated cold-adapted vaccine. The pandemic vaccines used in 2009 proved to be more immunogenic than expected from prepandemic vaccine trials, while the adverse events observed with AS03-adjuvanted vaccines call their future use into question. However, neither seasonal nor pandemic influenza vaccines can be regarded to be an ideal solution, because they have to be frequently adapted to new virus strains and they lack effectiveness in particular risk groups. They can be regarded as interim approaches to highly immunogenic vaccines that hopefully become available in the future. The underlying principles of future vaccines are also presented in this article.
[Show abstract][Hide abstract] ABSTRACT: A high priority in vaccine research is the development of influenza vaccines that do not use embryonated eggs as the substrate for vaccine production.
To determine the dose-related safety, immunogenicity, and protective efficacy of an experimental trivalent influenza virus hemagglutinin (rHA0) vaccine produced in insect cells using recombinant baculoviruses.
Randomized, double-blind, placebo-controlled clinical trial at 3 US academic medical centers during the 2004-2005 influenza season among 460 healthy adults without high-risk indications for influenza vaccine.
Participants were randomly assigned to receive a single injection of saline placebo (n = 154); 75 microg of an rHA0 vaccine containing 15 microg of hemagglutinin from influenza A/New Caledonia/20/99(H1N1) and influenza B/Jiangsu/10/03 virus and 45 microg of hemagglutinin from influenza A/Wyoming/3/03(H3N2) virus (n = 153); or 135 microg of rHA0 containing 45 microg of hemagglutinin each from all 3 components (n = 153). Serum samples were taken before and 30 days following immunization.
Primary safety end points were the rates and severity of solicited and unsolicited adverse events. Primary immunogenicity end points were the rates of 4-fold or greater increases in serum hemagglutinin inhibition antibody to each of the 3 vaccine strains before and 28 days after inoculation. The prespecified primary efficacy end point was culture-documented influenza illness, defined as development of influenza-like illness associated with influenza virus on a nasopharyngeal swab.
Rates of local and systemic adverse effects were low, and the rates of systemic adverse effects were not different in either vaccine group than in the placebo group. Hemagglutinin inhibition antibody responses to the H1 component were seen in 3% of placebo, 51% of 75-microg vaccine, and 67% of 135-microg vaccine recipients, while responses to B were seen in 4% of placebo, 65% of 75-microg vaccine, and 92% of 135-microg vaccine recipients. Responses to the H3 component occurred in 11% of placebo, 81% of 75-microg vaccine, and 77% of 135-microg vaccine recipients. Influenza infections in the study population were due to influenza B and A(H3N2), and influenza A infections were A/California/7/2004-like viruses, an antigenically drifted strain. Seven cases of culture-confirmed CDC-defined influenza-like illness occurred in 153 placebo recipients (4.6%) compared with 2 cases (1.3%) in 150 recipients of 75 microg of vaccine, and 0 cases in recipients of 135 microg of vaccine.
In this study, a trivalent rHA0 vaccine was safe and immunogenic in a healthy adult population. Preliminary evidence of protection against a drifted influenza A(H3N2) virus was obtained, but the sample size was small. Inclusion of a neuraminidase component did not appear to be required for protection.
clinicaltrials.gov Identifier: NCT00328107.
JAMA The Journal of the American Medical Association 04/2007; 297(14):1577-82. DOI:10.1001/jama.297.14.1577 · 35.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: No published meta-analyses have assessed efficacy and effectiveness of licensed influenza vaccines in the USA with sensitive and highly specific diagnostic tests to confirm influenza.
We searched Medline for randomised controlled trials assessing a relative reduction in influenza risk of all circulating influenza viruses during individual seasons after vaccination (efficacy) and observational studies meeting inclusion criteria (effectiveness). Eligible articles were published between Jan 1, 1967, and Feb 15, 2011, and used RT-PCR or culture for confirmation of influenza. We excluded some studies on the basis of study design and vaccine characteristics. We estimated random-effects pooled efficacy for trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV) when data were available for statistical analysis (eg, at least three studies that assessed comparable age groups).
We screened 5707 articles and identified 31 eligible studies (17 randomised controlled trials and 14 observational studies). Efficacy of TIV was shown in eight (67%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 59% [95% CI 51-67] in adults aged 18-65 years). No such trials met inclusion criteria for children aged 2-17 years or adults aged 65 years or older. Efficacy of LAIV was shown in nine (75%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 83% [69-91]) in children aged 6 months to 7 years. No such trials met inclusion criteria for children aged 8-17 years. Vaccine effectiveness was variable for seasonal influenza: six (35%) of 17 analyses in nine studies showed significant protection against medically attended influenza in the outpatient or inpatient setting. Median monovalent pandemic H1N1 vaccine effectiveness in five observational studies was 69% (range 60-93).
Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons. Evidence for protection in adults aged 65 years or older is lacking. LAIVs consistently show highest efficacy in young children (aged 6 months to 7 years). New vaccines with improved clinical efficacy and effectiveness are needed to further reduce influenza-related morbidity and mortality.
Alfred P Sloan Foundation.
[Show abstract][Hide abstract] ABSTRACT: The possible enhancement of anti-influenza A virus memory cytotoxic T cell (CTL) responses to inactivated influenza virus vaccine by coadministration of intranasal live attenuated influenza A virus vaccine was investigated. Fifty elderly nursing home residents received inactivated trivalent influenza virus vaccine intramuscularly and simultaneously were randomly assigned to receive either bivalent live attenuated influenza A virus vaccine or saline placebo intranasally in a blinded fashion. A larger proportion of volunteers who received live attenuated virus vaccine than of those who received placebo experienced a postvaccination rise in anti-influenza A virus CTL activity (15 of 23 vs. 8 of 24; P < .05). Anti-influenza A virus cytotoxicity was primarily mediated by CD8+ T cells and was influenza A virus-specific and HLA-restricted. There was a possible advantage of administering live attenuated with inactivated virus vaccine because of enhanced memory anti-influenza A virus CTL activity.
The Journal of Infectious Diseases 07/1995; 172(1):1-10. DOI:10.1093/infdis/172.1.1 · 6.00 Impact Factor
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