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The need for yearly updates and the low coverage of existing influenza vaccines has created an unmet need for products providing a wider and longer-lasting immunity. Several companies are therefore developing "universal" influenza vaccines that make annual vaccination unnecessary, mainly targeting the highly conserved M2e domain of the virus, although doubts regarding their real benefits remain.
Awareness for the severity of influenza is increasing
Influenza is a highly contagious disease with a huge clinical and economical impact. In the US alone, 60 million people per year become infected, leading to 200,000-400,000 hospitalizations and 35,000-70,000 deaths, mainly among the elderly and very young children (CDC, 2006). Influenza kills as many Americans as breast cancer and two to three times more than HIV/AIDS, with annual direct and indirect costs, including lost work days, estimated at $12-14 billion for severe flu epidemics.
Fuelled by the H5N1 pandemic influenza threat, which has caused huge public attention, awareness for influenza and its complications has been growing over the recent years. As a result, healthcare authorities around the world have been eager to extend vaccination recommendations for seasonal influenza. The US is leading the field, having broadened recommendations to include small children aged 6-59 months, chronically ill, pregnant women, healthcare workers, elderly aged 50 years and over as well as all household contacts of all risk groups during the influenza season 2006/07. This has increased the total number of persons advised to receive a flu shot in the country to approximately 218 million (CDC, 2006a).
Currently available vaccines have to be updated yearly and do not always match the circulating strains
Currently available influenza vaccines are using two proteins on the virus surface, hemagglutinin (H) and neuraminidase (N) as antigens to produce a protective immune response. However, both H and N are subject to frequent mutations due to high selective pressure on the virus. Therefore, influenza strains in circulation differ significantly in their H and N patterns. As currently available vaccines only provide protection against specific H/N combinations, they need to be updated on a yearly basis to include the currently circulating strains.
Hedwig Kresse, infectious diseases analyst at Datamonitor, says: "The need for yearly vaccine updates leads to huge costs and long development times, and is always associated with the risk of launching a vaccine formulation that does not match the actual circulating strain once the flu season has begun." In addition, the development of a conventional vaccine with guaranteed efficacy against a potential pandemic flu would be impossible before the identification of the exact H/N composition of the pandemic virus - which is likely to be after an outbreak. The ideal way to avoid this dangerous delay would be the development of a so-called "universal vaccine" that provides protection against all influenza strains and does not need to be updated yearly.
M2e is the most promising target for a universal influenza vaccine
The most popular approach for the development of a universal influenza vaccine is to target the ectodomain of the M2 protein, a proton channel which spans the lipid bilayer membrane of the influenza virus. The external domain, M2e, is 23-amino acids long and only weakly immunogenic on its own. But when presented on an appropriate carrier or with an adjuvant, it induces a high titer antibody response, which, in mice, effectively protects against a potentially lethal influenza infection. M2 is highly conserved in influenza A viruses - despite numerous epidemics and several pandemics, its sequence has hardly changed since the first influenza virus was isolated in 1933.
Several companies are developing M2e vaccine candidates in clinical stages
The obvious advantages and the promising commercial opportunities of a universal influenza vaccine have led several, mainly small and mid-size biotech companies, to embark on the development of M2 candidates.
Acambis, a biotechnology company based in Cambridge , UK and Cambridge, MA, is developing ACAM-FLU-A, a recombinant vaccine that uses a hepatitis B core protein to deliver M2e. The candidate was the first universal vaccine to enter Phase I clinical trials in July 2007 following encouraging results in mice. In addition, two adjuvants, enhancing the immune response caused by vaccination, will be evaluated, one of them being Antigenics' QS-21.
VaxInnate, based in Cranbury, NJ, is also developing an M2e candidate vaccine, which advanced into Phase I clinical trials in September 2007. The company applies a two-fold approach: the vaccine contains recombinant flagellin, a bacterial toll-like-receptor (TLR) agonist that triggers the innate immune system and thereby causes an immediate non-specific response. By coupling flagellin to the M2e antigen, the targeted antibody response to the vaccine's antigen is enhanced by the simultaneous stimulation of the innate immune system through flagellin, which could result in a more protective and longer lasting immunity.
In addition, VaxInnate's fusion vaccine can be efficiently and economically manufactured in bacteria, a process which is faster and cheaper than conventional flu vaccine manufacturing in chicken eggs. However, it will have to be determined in clinical studies if production of the vaccine in a non-eucaryotic expression system affects the immunogenicity of the vaccine. VaxInnate is now enrolling up to 60 volunteers in a Phase I study of two doses injected 28 days apart. Data regarding the safety and immunity observed in this trial, which is supported by a $9.5 million grant from the Bill & Melinda Gates Foundation, are expected for spring 2008.
Other companies working on M2e vaccines include California-based Dynavax, which is taking an adjuvant-enhanced approach to universal vaccination that is regarded as highly promising, as well as a co-operative project involving Biovitrum AB/Pepscan Systems BV/Proxima Concepts Ltd. Merck is also working on a universal vaccine based on targeting M2.
Potential of universal vaccines is questionable despite advances
Although universal vaccines seem a highly promising idea in theory and good preclinical results encourage further development, there are doubts regarding the real efficacy of M2 candidates and the feasibility of universal influenza vaccination. Influenza is a virus with a very high mutation rate, and although M2e has been shown to be highly conserved so far, this may be partially caused by the low selective pressure on this component of the virus, as current vaccines are targeting H and N.
If M2e becomes a direct target for immunization, the protein may undergo mutations similar to those observed for H and N, rendering the potential superior breadth of coverage of M2e vaccines obsolete. In addition, a vaccine based on the M2e antigen will almost certainly have to contain a potent adjuvant due to the low immunogenicity of M2e itself. However, the safety profile as well as the ability of currently used adjuvants to sufficiently boost the immune response will have to be investigated in clinical trials. Another open question is whether and in what intervals booster shots would be needed for patients immunized with the weakly immunogenic M2e.
Kresse summarizes: "Even if M2e vaccines may not change the need for regular influenza vaccination, they could potentially provide protection against a larger number of influenza A strains than currently available trivalent vaccines, provided that mutation rates of M2e remain low. This could be of particular benefit in developing countries and for pandemic flu prevention."
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