4th quarter 2006
Development of vaccines against the influenza virus that will cause the next pandemic
Faced with the threat of a global influenza pandemic, governments, international organizations and vaccine producers are collaborating on the goal of novel vaccine development and production techniques.
Several governments have bought millions of doses of vaccine against the avian influenza virus H5N1 which occasionally spread to humans. However, there remain a lot of open questions. Will the next influenza pandemic be caused by a H5N1-based or another influenza virus? If not H5N1-based: The vaccine stock might be useless. If H5N1-based: How different is the pandemic virus from the original H5N1? The more different, the less likely the H5N1 vaccine will work.
Since nobody knows the answers on above questions and even probabilities cannot be calculated, further influenza pandemic prevention strategies are necessary. Once an influenza virus has mutated into a form that can spread from human to human, the risk of a pandemic is very high. It then is critical to get a vaccine as soon as possible. If the stored H5N1 vaccine does not work, a new one has to be developed. Using "reverse genetics" under optimal conditions (e.g. producing cells are prepared in advance and just get the critical novel genes of the pandemic candidate virus inserted; production capacity is available; some safety and regulatory tests were already performed), significant amounts of vaccine could be produced within weeks.
It is as good as sure that one day a new influenza pandemic will start. All other questions are open. Only after the next influenza pandemic, we will have the data to definitely answer the questions of today.
The major problems
To successfully target the virus, it must be known. Today, it appears likely that it will be derived from the H5N1 avian influenza virus (AIV) but this is not sure. The recent avian influenza concerns first arose in 1997, when the H5N1 avian influenza virus first moved into humans. In 1999, two years after the first concerns over H5N1, another novel avian flu virus, H9N2, caused illness in Hong Kong. It reappeared in 2003. However, AIVs of the other subtypes must not be ignored. All AIVs have pandemic potential.
Flu viruses change over time (a process known as "antigenic drift"), which is mostly reflected in accumulating changes in the H antigen. Unfortunately, predicting the change of the viral H antigen has not been reliable. Thus, predicting the emergence of a particular pandemic strain (avian or otherwise) is unlikely.
Even if the next pandemic will come from H5N1, nobody knows if it then will have accumulated just a few point mutations or if it will have recombined with other influenza viruses. The more differences exist between the vaccinating virus and the spreading virus, the less likely a vaccinated individual can fight the virus successfully.
If a distinct influenza virus should suddenly emerge, an additional new vaccine against that strain may be needed. But to develop this probably costs more time than a pandemic is lasting. Therefore, starting the development only once the causal virus is identified would bring the successful vaccine too late. This dilemma is approached by governments, public health organizations (CDC, RKI, …) and WHO now by first preparing against H5N1. There is hope that vaccines targeted at today’s avian H5N1 virus will at least partially give immunity against a future human H5N1 virus. In addition, an established and well prepared infrastructure (e.g. having enough seed virus that only needs to have added the specific antigen, probably its H antigen) could produce significant amounts of appropriate vaccine against the future human H5N1 virus within the critical time frame. Ultimately, the experience gained by manufacturers in producing the current H5N1 vaccine should make us better prepared for the next time.
H5N1 flu vaccine clinical trials in the USA
The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has begun a series of clinical trials to evaluate H5N1 vaccine candidates. In 2004, NIAID provided an inactivated H5N1 reference virus that was highly lethal to both birds and humans to Sanofi-Pasteur and Chiron for vaccine production. The process used to manufacture the Sanofi-Pasteur H5N1 influenza vaccine is similar to that used to make the seasonal influenza vaccine that is used in the United States each year. Because the processes are similar, the FDA will more easily be able to evaluate this candidate H5N1 vaccine.
The first clinical trial tested the H5N1 vaccine produced by Sanofi-Pasteur in 451 healthy adults. This trial evaluated the safety of the vaccine and its ability to generate an immune response. A report in the March 30th issue of the New England Journal of Medicine showed that the H5N1 candidate vaccine is safe and a 2-dose schedule of 90-µg doses generated the highest immune response among those doses tested. Similar trials to evaluate the safety and immunogenicity of the Sanofi-Pasteur H5N1 vaccine in persons 65 and older and in children ages 2 through 9 years old are under way.
Vaccines against H5N1 already delivered or in production
Several governments have bought millions of doses of vaccine against the avian influenza virus H5N1 which occasionally spread to humans. Chiron in October 2005 announced that it has won a $62.5 million contract to supply the US government with pre-pandemic influenza vaccine for a stockpile. The vaccine is based on an inactivated influenza strain provided by the National Institute of Allergy and Infectious Diseases (NIAID). The vaccine contributes to the U.S. National Strategic Stockpile (enough avian influenza vaccine for 20 million people and enough antiviral medication for another 20 million people).
In February 2006, Chiron announced that it has entered into a supply contract with the UK government for the same pre-pandemic influenza vaccine containing Chiron’s MF59 adjuvant.
Alternative and advanced strategies to develop vaccines for pandemic influenza
The classical and proven principle behind influenza vaccines is to elicit protective antibodies directed against H antigen (and to a lesser extent N antigen), the major antigen of the virus that induces neutralizing antibodies. The vaccine strain must closely match the circulating strain.
Vaccines created against H9N2 and H5 subtypes of AIV or against purified recombinant H5 antigen were poorly immunogenic in comparison to those created against the "old" human influenza strains H1N1 and H3N2. For example, inactivated vaccines against avian influenza subtypes require 2 doses and administration with adjuvant to achieve the desired level of neutralizing antibody.
One current approach is the design of vaccines that induce a cross-reactive response in the vaccinated host. Immunization with the N antigen is likely to induce responses that are more cross-reactive than those by the more variable H antigen. In both cases, however, protection will require immune responses that are more vigorous than what is seen after natural infection. Antibodies against N antigen in infected humans are generally not protective. Thus vaccines consisting of N antigens would need to be made to induce a dramatically enhanced immune response.
Alternatively, genetically engineered viruses could be generated, which would express several variant antigens or epitopes, thereby achieving a more cross-protective immunization. Chimeric H antigen recombinant viruses have recently been described. Such genetically engineered viruses may present several conserved immunogenic epitopes on the viral surface, which would be a first step toward a more universal influenza vaccine.