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 WORKING PAPERRESEARCH FOR THE DEVELOPMENTOF AN INFLUENZA PANDEMIC VACCINE
Working Group 3 of the Consultation for the development of a global action plan toincrease supply of influenza pandemic vaccines, WHO, Geneva, 2-3 May 2006
 
Introduction
Vaccination is considered a key component of the strategy to respond to an influenzapandemic, with the aim to reduce morbidity and mortality, and to curb the spread of the diseaseCurrently available inactivated vaccines are effective in the majority of populationswhen they contain antigens that are well matched with those in the circulating viralstrains. A modification of vaccine composition is necessary almost every year tofollow antigenic changes of circulating viruses and annual immunization isrecommended for groups decided to be at increased risk of severe disease.Whileconsiderable effort is being made to develop and evaluate candidate H5N1 vaccinesbased on existing technologies, there is a need for the development of vaccines thatcan overcome some of the limitations of the existing candidates. In 2004, the WHOInitiative for Vaccine Research established a research programme with the followingobjects: the development of new influenza vaccines that induce broad-spectrum andlong-lasting immune responses and to coordinate research projects that will contributeto the acceleration of the development of influenza pandemic vaccines.
Generation of new vaccines
The main objective is to develop safe and effective influenza vaccines that inducebroad-spectrum (cross protection within subtypes and/or heterosubtypic immunity),long-lasting protection against influenza and its sequelae preferably with a singledose. .Vaccines that induce broad immunity would probably not have to be updatedannually, since they would protect against viruses with antigenically distinct HAmolecules. This would allow the preparation of vaccine lots in advance and wouldmake the logistics for vaccine production easier. The development of some vaccinesmay also result in improved efficacy in certain high-risk groups, such as the elderly.There are several strategies that can be used for the development of such broadlyprotective vaccines.
Live attenuated vaccines
A review of the data on live attenuated vaccines (LAIV) demonstrates a history of safety, protection against homologous virus and minor variants, evidence of herdimmunity through vaccination of children and the early onset of protection possiblydue to an interferon response. There is some evidence that LAIV might be moreefficacious than inactivated vaccines. In animal studies it was shown that LAIVinduced broad immunity against various variants of the H5 subtype and furtherevaluation of candidate pandemic vaccines for H5 and H9 viruses in humans is now inprogress. However the safety and efficacy of LAIVs in patients with asthma, theimmunocompromised, the very young or elderly awaits confirmation. It is unclear,
 
 2whether pre-pandemic use of live vaccines containing novel HA subtypes couldrepresent a risk of generating undesirable reassortants with pandemic potential. Also,the use of reassortant DNA technology to prepare LAIV presents regulatory issues insome countries.
Vaccines that target conserved influenza virus proteins
Some viral proteins like the matrix proteins M1 and M2 and the nucleoprotein (NP)are relatively conserved and are considered potential targets for the induction of broadprotective immunity. Studies in animals have shown that experimental vaccines basedon these proteins can induce cross-protective immunity against different subtypes of human influenza A viruses.
 M2 protein
The M2 protein is expressed on the membrane of infected cells and protectioninduced by this protein is probably mediated through antibody dependent cellmediated cytotoxicity (ADCC). A number of approaches have been used to enhanceimmune responses to M2, including fusion with various proteins and delivery usingviral vector or in virus-like particles. In animals, M2-based vaccines induced broadprotection against different subtypes of influenza A virus. However, M2 is not presentin influenza B viruses and will thus not contribute to protective immunity against thisgroup of viruses. In addition, while the sequence of the M2 protein is highlyconserved between influenza A viruses, it demonstrates species specificity. Furtherstudies are required to determine whether an M2-based vaccine could be sufficient toprotect against severe influenza and death or whether they should be considered as asupplement to existing inactivated vaccines.
 M1 and NP proteins
M1 and NP are major targets for virus-specific cytotoxic T lymphocytes (CTL) andconsidered candidates for the induction of cross-protective immunity. Indeed it hasbeen shown in animal models and humans that virus-specific CTL contribute toprotective immunity against influenza virus infection. NP-based vaccines providedprotection against different subtypes of influenza A viruses in mice and NP-expressing plasmid vaccines induced virus specific CTL and protective immunityagainst challenge infection. For the induction of CTL responses it is essential that theprotein of interest is processed in antigen presenting cells via the endogenous route of antigen processing. The required delivery of protein into the cytoplasm can beachieved with live viral vector, allowing
de novo
synthesis of protein in thecytoplasm, or the use of specialized antigen delivery forms.
Mucosal application of inactivated vaccines
Alternative routes of vaccination include the mucosal delivery, which has thepotential advantages of being non invasive and inducing both local and systemicimmune responses.Mucosal vaccination with live or inactivated vaccines is better forthe induction of local IgA responses in the upper respiratory tract, which contributesto protective immunity and might be useful in strategies using vaccine to limittransmission of influenza. In addition, it has been suggested that IgA antibodyresponses are more broadly reactive than IgG antibody responses. The potential valuefor aerosol vaccination that would deliver vaccine to both the upper and lower respiratory tracts is being assessed in some studies.
 
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New adjuvants
The development of new inactivated pandemic vaccines and especially those based onpurified antigens has been hampered for a long time by low immunogenicity of antigens and by the lack of safe and efficacious adjuvants. Many studies are inprogress to identify appropriate immune-stimulating substance and their advantagesand drawbacks becomes more apparent. There is need to have more information onmechanisms of action of particular adjuvants because it could open the way forcombining some of them to reach synergistic effects on immune responses andeliminate adverse reactions.
Alternative sources of HA antigen
Traditionally, influenza vaccines are produced in embryonated chicken eggs, which isnot conducive to up scaling of production volume. In addition, the productioncapacity of the vaccine manufacturers is limited and insufficient to allow a globalvaccination campaign and an increase in global production capacity and investment inalternative production systems is very desirable. Recently, cell culture systems havebeen approved for vaccine production, may which allow flexible vaccine productionand upscaling. In addition, recombinant HAs expressed by baculoviruses arecurrently being evaluated and these preparations induced antibody responses andprotective immunity comparable to that induced by conventional vaccines. Recentstudies in mice have shown that an adenovirus-based vaccine harbouring expressioncassettes for H5N1 antigen provided protection against challenge with homologousvirus. Caution is required in interpreting these results as history has shown that mousedata does not always predict the performance of a vaccine in humans.
Regulatory issues
There are a range of regulatory issues in gaining acceptance of new influenzavaccines, many of these defined in existing WHO Technical Reports and otherdocuments. Greater international consistency in licensing requirements is desirable.WHO can facilitate coordination among regulatory authorities to develop harmonizedprocedures for vaccine registration.
 
Immunological Issues
Improvement of priming of immune responses
A current concern is that it may be difficult to prepare effective vaccines containingHA molecules of a subtype to which no immunity exists in the general population.Further studies should help to identify methods to effectively induce and measurepriming. There is a great demand for adjuvant systems that could improve the primaryimmune responses induced by the current or future influenza vaccines and that aresafe.
Immunological mechanisms of protection, laboratory correlates of protection
Traditionally, hemagglutination-inhibiting (HI) antibodies have been used as acorrelate of protection and titers of > 40 are considered protective. For novel subtypeslike H5, HI assays have proven difficult and virus neutralization assays (VN) arebeing performed although the levels that correlate with protection have not beenestablished. Since cell mediated immunity is also a component of protection and canbe induced by certain types of vaccines (such as LAIV which generally producemodest HI or VN responses), the demonstration of virus-specific T-cell mediated
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