Two new phase 1 human trials suggest that initial (prime) immunisation with a DNA vaccine against H5N1 influenza followed by a booster dose of conventional influenza vaccine is more effective than giving two doses of traditional influenza vaccines. The findings, published Online First in The Lancet Infectious Diseases, indicate that this strategy could be used to prepare for future pandemics.
The main threat of a global influenza outbreak is that people might not have pre-existing immunity to the emerging virus strain. The development and distribution of effective vaccines is vital to preventing the spread of a future pandemic. Because the general population is largely naïve to H5N1 influenza, the H5 antigen is ideal to test novel approaches to enhancing the protection of influenza vaccines.
Two phase 1 trials conducted by Julie Ledgerwood and colleagues from the National Institutes of Health, Bethesda, MD, USA, were designed to assess the safety and immune responses of a prime-boost influenza vaccination strategy. The prime consisted of a vaccine made from DNA encoding the haemagglutinin (HA)* from a H5N1 influenza virus, followed by a booster dose of the H5N1 monovalent inactivated vaccine (MIV).
The researchers randomly assigned 81 healthy adults with no history of influenza vaccination to receive a dose of the DNA vaccine at day 0 or twice, at day 0 and week 4, followed by a MIV booster at 4 or 24 weeks, or a two-dose regimen of MIV with either a 4 or 24 week interval.
Overall, the prime-boost strategy was safe and greatly enhanced immune response, especially when the time between the prime and the boost was extended to 24 weeks.
Antibodies induced by DNA priming with a 24-week MIV boost interval reached protective levels in 81% of individuals, and the increase in geometric mean antibody titre (a measure of immune response) was more than four times that of individuals given only MIV at 4 or 24 weeks.
Importantly, in several individuals the prime-boost regimen also stimulated the production of neutralising antibodies that targeted the stem region of the HA protein. The stem varies little across different strains of the virus and therefore antibodies generated against the stem are able to neutralise multiple influenza virus strains.
The authors say: "A DNA-MIV vaccine regimen could enhance the efficacy of H5 or other influenza vaccines and shows that anti-stem antibodies can be elicited by vaccination in man."
"These findings are especially important because a major limiting factor in the preparation against pandemic influenza is the restricted manufacturing capacity to produce enough doses of vaccines in a short period of time to cover the population in need. If the vaccination strategy presented in this study was followed, the total amount of traditional vaccines against influenza would be reduced by half, which would allow more individuals to be vaccinated in a timely manner", explains Shan Lu from the University of Massachusetts Medical School, Worcester, MA, USA, in an accompanying Comment.
He adds: "The report supports the idea of a prepandemic vaccination, since various DNA vaccines can easily be mixed together to provide broad coverage against several potential pandemic influenza viruses (even across different subtypes), long before any outbreak. Hosts primed with DNA vaccines are very likely to have reduced morbidity and mortality, even without a boost."
Dr Julie Ledgerwood, National Institutes of Health, Bethesda, USA. Via NIAID Office of Communications T) +1 301 402 1663 E) niaidnews@niaid.nih.gov
Dr Shan Lu, University of Massachusetts Medical School, Worcester, USA. Via Cindi Callaghan T) +1 508 856 6791 E) Cindi.Callaghan@umassmed.edu
Notes to editors: *HA is the protein that allows the influenza virus to bind to and infect the body's normal cells. Antibodies that bind to the HA protein can neutralise the virus.
Journal
The Lancet Infectious Diseases