Prospects for universal influenza virus vaccine.
The current vaccination strategy against influenza A influenza A
Influenza caused by infection with a strain of influenza virus type A.
influenza A Infectious disease An avian virus, especially of ducks–which in China live near the pig reservoir and 'vector'; and B viruses is vulnerable to the unanticipated emergence of epidemic strains that are poorly matched by the vaccine. A vaccine that is less sensitive to the antigenic evolution of the virus would be a major improvement. The general feasibility of this goal is supported by studies in animal models that show that immunologic activities directed against relatively invariant (programming) invariant - A rule, such as the ordering of an ordered list or heap, that applies throughout the life of a data structure or procedure. Each change to the data structure must maintain the correctness of the invariant. viral determinants can reduce illness and death. The most promising approaches are based on antibodies specific for the relatively conserved ectodomain of matrix protein 2 and the intersubunit region of hemagglutinin hemagglutinin /he·mag·glu·ti·nin/ (-gloo´ti-nin) an antibody that causes agglutination of erythrocytes.
cold hemagglutinin one which acts only at temperatures near 4° C. . However, additional conserved determinants for protective antibodies are likely to exist, and their identification should be encouraged. Most importantly, infection and current vaccines do not appear to effectively induce these antibodies in humans. This finding provides a powerful rationale for testing the protective activity of these relatively conserved viral components in humans.
Current influenza virus vaccines attempt to induce strong antibody responses against the viral glycoproteins hemagglutinin (HA) and, with lesser emphasis, neuraminidase neuraminidase /neu·ra·min·i·dase/ (-ah-min´i-das) an enzyme of the surface coat of myxoviruses that destroys the neuraminic acid of the cell surface during attachment, thereby preventing hemagglutination. (NA) because their protective efficacy is well documented. Thus, typical HA-specific antibodies neutralize viral infectivity and fully protect against infection when they are present at sufficient concentration in the lining fluid of the respiratory tract respiratory tract
The air passages from the nose to the pulmonary alveoli, including the pharynx, larynx, trachea, and bronchi.
Respiratory tract , and typical NA-specific antibodies inhibit the release of newly formed virus from infected host cells and thus limit the spread and shedding of virus during infection. Current vaccines are highly effective in children and adults (70%-90%), although not in those [greater than or equal to] 65 years of age (30%-50%) (1). Apart from their limited efficacy in the elderly, a major drawback of current vaccines is that the principal vaccine targets, most notably the distal region of HA, are subject to continuous alteration in circulating epidemic virus strains (2,3). This process, termed antigenic drift antigenic drift (an´tējen´ik),
n the ability of viruses to alter their genetic makeup, thereby creating mutant antigens and bypassing the antibody barrier of the host. , results from the high mutation rate of the viral genome and the continuous selection of mutants with improved replication characteristics in the immune human host population. On average, the prevalent influenza A virus strain acquires 3-4 amino acid amino acid (əmē`nō), any one of a class of simple organic compounds containing carbon, hydrogen, oxygen, nitrogen, and in certain cases sulfur. These compounds are the building blocks of proteins. changes per year in HA, with most being located in the regions recognized by protective antibodies. Every 2 to 5 years, the accumulation of mutations results in a major antigenic drift away from the previously circulating strains (4). A more drastic antigenic change, termed antigenic shift antigenic shift
A sudden, major change in the antigenic structure of a virus, usually the result of genetic mutation. , occurs if a new HA subtype (programming) subtype - If S is a subtype of T then an expression of type S may be used anywhere that one of type T can and an implicit type conversion will be applied to convert it to type T. is introduced into the pool of human virus strains by reassortment of genes between animal and human strains or by direct transmission of strains from an animal reservoir to humans, as has occurred recently with strains of H5N1, H7N7, and H9N2 (1). Accordingly, the influenza vaccine influenza vaccine Flu vaccine A vaccine recommended for those at high risk for serious complications from influenza: > age 65; Pts with chronic diseases of heart, lung or kidneys, DM, immunosuppression, severe anemia, nursing home and other chronic-care must be updated on a regular basis to reflect the antigenic changes that occur in the pool of circulating virus strains. Because vaccines have to be manufactured before the actual epidemic strains are known, a failure to anticipate emergence of a strain with major antigenic drift or shift relative to the vaccine will result in a substantial reduction or abrogation The destruction or annulling of a former law by an act of the legislative power, by constitutional authority, or by usage. It stands opposed to rogation; and is distinguished from derogation, which implies the taking away of only some part of a law; from Subrogation, of vaccine-mediated protection.
While antibodies to the immunodominant, but highly variable, regions of HA and NA can provide potent virus strain-specific protection, the existence of weaker and more broadly protective immune activities directed to less variable regions of viral proteins has long been known (5). These protective activities have collectively been termed heterotypic heterotypic /het·ero·typ·ic/ (-tip´ik) pertaining to, characteristic of, or belonging to a different type.
het·er·o·typ·ic or het·er·o·typ·i·cal
adj. or heterosubtypic immunity because they provide a measure of protection against viruses of distinct subtypes. Because of their potential for broadening vaccine-mediated protection in humans, they have been studied extensively in animals and found to be mediated predominantly by virus-specific memory T cells T cells
A type of white blood cell produced in the thymus gland. T cells are an important part of the immune system. Infants born with an underdeveloped or absent thymus do not have a normal level of T cells in their blood. (6,7), antibodies (8-10), or a combination of both (11-13). The reason for these differences in the relative strength of T-cell and antibody-mediated protection is not clear but could be attributable to differences in vaccination procedures, virus challenge, and read out (how protection was measured) between the various studies. Pros and cons pros and cons
the advantages and disadvantages of a situation [Latin pro for + con(tra) against] of some of these activities in terms of their potential for development of a broadly protective, "universal" influenza vaccine are briefly discussed below.
Memory T Cells
A large fraction of the virus-specific T-cell response in mice and humans is directed to conserved determinants of viral core proteins, and many studies in mice have shown that memory T cells can accelerate recovery and reduce illness on virus challenge. Cytotoxic T (Tc) cells were found to be more protective than helper T cells, and among Tc cells, protective activity was shown to depend on their frequency (number of virus-specific cells/total cells), cytokine Cytokine
Any of a group of soluble proteins that are released by a cell to send messages which are delivered to the same cell (autocrine), an adjacent cell (paracrine), or a distant cell (endocrine). secretion profile, memory type (central vs. effector effector /ef·fec·tor/ (e-fek´ter)
1. an agent that mediates a specific effect.
2. an organ that produces an effect in response to nerve stimulation. ), and even fine specificity. However, in contrast to findings in mice, the protective value of memory Tc cells in humans remains controversial. The classic study by McMichael et al. (14) indicated that presence of memory Tc cells in blood, which could give rise to Tc cells on stimulation in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment.
In an artificial environment outside a living organism. , correlated with reduced virus shedding virus shedding
Excretion of virus from the infected host by any route. 3-4 days after volunteers were challenged with a wild-type virus, but had no significant effect on illness. Subsequent studies performed in children found no significant difference in shedding of attenuated Attenuated
Alive but weakened; an attenuated microorganism can no longer produce disease.
Mentioned in: Tuberculin Skin Test
having undergone a process of attenuation. vaccine strains in patients who had recovered from previous infection with a vaccine or natural strain of a different subtype than did study participants who had no evidence of previous virus exposure (15,16). Similarly, children vaccinated with an H1N1 strain showed no difference in attack rate and febrile febrile /feb·rile/ (feb´ril) pertaining to or characterized by fever.
Of, relating to, or characterized by fever; feverish. respiratory illness during exposure to natural epidemic H3N2 virus from controls who received a placebo (17).
Although the presence of memory Tc cells in the vaccinated children was not demonstrated experimentally, it can be implied based on findings that infection with a live, attenuated vaccine or natural virus strain typically stimulates a Tc-cell response in humans. Taken together with the observation that the degree of antigenic change (drift, shift) is a major determinant of epidemic severity, little evidence exists for a substantial protective role of subtype cross-reactive memory Tc cells in human influenza virus influenza virus
Any of three viruses of the genus Influenzavirus designated type A, type B, and type C, that cause influenza and influenzalike infections. infection; the contribution of Tc cells per se in the control of the infection is not questioned, only whether memory Tc cells provide a further improvement.
Vaccine-induced or natural upper respiratory tract infection upper respiratory tract infection URI Infectious disease A nonspecific term used to describe acute infections involving the nose, paranasal sinuses, pharynx, and larynx, the prototypic URI is the common cold; flu/influenza is a systemic illness involving the URT in humans may not engender an optimally protective memory Tc-cell population because of insufficient number or composition. However, a large number of memory T cells may also result in immunopathologic manifestations (14,18), which tend to be associated with excessive inflammatory responses in acute infections. Thus, a universal vaccine based on the induction of a strong memory Tc response might necessitate a difficult balancing act between protection and immunopathologic changes. Unless one can identify a particularly protective memory-Tc-cell population that is poorly induced by natural or vaccine-induced infection, the nondiscriminatory enhancement of memory T-cell populations may not be a promising approach for a universal influenza vaccine.
Antibodies Specific for Conserved Viral Determinants
A precondition for antibody-mediated protection is the accessibility of the viral antigen viral antigen
n. Abbr. VA
An antigen with multiple antigenicities that is protein in nature, strain-specific, and closely associated with the virus particle. to antibody on infectious virus particles, intact infected cells, or both. This accessibility restricts the potential targets to conserved structures of the ectodomains of viral transmembrane proteins HA, NA, and M2, in the case of influenza A viruses, and HA, NA, NB, and BM2, in the case of influenza B influenza B
Influenza caused by infection with influenza virus type B.
influenza B Infectious disease An influenza virus which causes epidemics in 3-5 yr cycles. Cf Influenza A, Influenza C. viruses. Results of studies reported thus far have focused on M2 of influenza A and HA of influenza A and B viruses.
M2 of Influenza A Viruses
M2 forms tetramers that exhibit pH-inducible proton transport activity. It regulates the pH of the viral core after virus uptake into the host cell's endosomal compartment during initiation of infection and subsequently of vesicles that transport the viral transmembrane proteins to the cell surface during the late stage of infection. M2 tetramers are expressed at high density in the plasma membrane plasma membrane
See cell membrane. of infected cells and are well accessible to M2e-specific antibodies in this location, but only a few copies become incorporated into the envelope of mature infectious virus particles (19,20). M2 has a small, nonglycosylated ectodomain (M2e) of 23 amino acids (aa), not counting the posttranslationally removed N-terminal Met. This region has shown only limited variation among human influenza A viruses. This remarkable degree of structural conservation of M2e is attributable mainly to its genetic relation with matrix protein 1 (Ml), the most conserved protein of influenza A viruses with which it shares coding sequences. Thus, aa residues 1-9 of M2e and Ml are encoded by the same nucleotides in the same reading frame and aa 10-23 of M2e and 239-252 of M1 in a different reading frame.
Studies by several groups conducted in mice and ferrets have shown that M2e-specific antibodies, while they did not prevent infection, restricted subsequent virus replication and reduced illness and proportion of deaths (20-24). This antibody response was only poorly induced by infection, both in mice (22) and humans (24,25). A likely reason for the poor M2e-specific antibody response is extensive antigenic competition with HA- and NA-specific responses (26). Thus, in view of the >10-fold difference in ectodomain size, the frequency of M2e-specific precursor B cells must be orders of magnitude lower than the frequencies of HA- and NA-specific precursor B cells. Assuming that most immunogenic im·mu·no·gen·ic
Producing an immune response.
producing immunity; evoking an immune response. entities generated in the course of infection contain a mixture of all 3 transmembrane proteins, most M2e may be taken up by HA- and NA-specific B cells, leaving little or none for B-cell receptor-mediated uptake and processing by M2e-specific precursor B cells. Note that the same phenomenon results also in a suppression of the NA-specific antibody response by immunodominant HA-specific B cells (26). Such competition can be avoided by presenting individual antigens on physically distinct immunogenic entities to the immune system immune system
Cells, cell products, organs, and structures of the body involved in the detection and destruction of foreign invaders, such as bacteria, viruses, and cancer cells. Immunity is based on the system's ability to launch a defense against such invaders. (27). The substantial M2e-specific antibody responses seen in mice after vaccination with dedicated M2e vaccines (20-24) supports the above explanation.
In view of the poor or absent M2e-specific antibody response in humans, confirming the genetic stability of M2e was essential when the virus was propagated in an immune environment. Replication of A/PR/8/34(H1N1) (PR8) virus for >3 weeks in severe combined immunodeficient (SCID SCID severe combined immunodeficiency (disease); see under immunodeficiency.
severe combined immunodeficiency
severe combined immunodeficiency disease. ) mice that were chronically treated with M2e-specific monoclonal antibodies (MAbs) resulted in the emergence of M2e-escape mutants (28). However, only 2 distinct escape mutants emerged, 1 with a replacement of Pro at position 10 by Leu Leu leucine.
leucine. (P10L) and the other with a replacement of the same Pro by His (P10H) (28). Each of these mutants was isolated repetitively from many distinct mice treated with distinct M2e-specific MAbs, which indicates that they represented essentially the entire range of escape mutants capable of arising from the PR8 wild-type virus under the given experimental conditions. No escape mutants emerged after 11 consecutive passages of PR8 in BALB/c mice that had been actively vaccinated with M2e (unpub. data). In addition, incorporating determinants of potential escape mutants into a polyvalent polyvalent /poly·va·lent/ (-va´lent) multivalent.
1. Acting against or interacting with more than one kind of antigen, antibody, toxin, or microorganism.
2. universal M2e vaccine would likely further impede emergence of escape mutants. Indeed, preliminary studies have shown that no escape mutants emerged in SCID mice treated with a combination of MAbs specific for M2e of wild-type PR8 and the P10H and P10L escape mutants (unpub. data). Thus, although M2e is not totally invariant, it is remarkably stable, even under immune pressure.
Several vaccination strategies have been evaluated in mouse and ferret models, including M2-expressing recombinant viruses, M2 recombinant proteins (20,21), M2-encoding plasmid DNA (29), and synthetic M2e peptides that were chemically linked to carrier proteins or synthetically linked to defined helper T-cell determinants (22-24). In most studies in which induction of an antibody response was confirmed, M2e-specific immunity reduced illness, but did not entirely prevent it. The best protection was reported for mice vaccinated by the intranasal route with an M2e-hepatitis B core fusion protein construct and detoxified heat-labile Escherichia coli Escherichia coli (ĕsh'ərĭk`ēə kō`lī), common bacterium that normally inhabits the intestinal tracts of humans and animals, but can cause infection in other parts of the body, especially the urinary tract. enterotoxin enterotoxin /en·tero·tox·in/ (en´ter-o-tok?sin)
1. a toxin specific for the cells of the intestinal mucosa.
2. a toxin arising in the intestine.
3. adjuvant adjuvant /ad·ju·vant/ (aj?dbobr-vant) (a-joo´vant)
1. assisting or aiding.
2. a substance that aids another, such as an auxiliary remedy.
3. ; almost none of these mice died after a virus challenge that killed 90% of control mice (21). However, in contrast to the significant protection seen in most mouse models, pigs vaccinated with recombinant M2e-hepatitis B core protein or plasmid DNA encoding an M2e-nucleoprotein fusion protein showed no protection or even had higher death rates, respectively, after virus challenge (29). This finding needs to be confirmed, and the explanation for it remains unknown. At this time, it serves as a reminder that immune phenomena are complex and that observations made in 1 species may not apply to another. By the same token, good protection in an animal model does not guarantee protection in humans.
Taken together, the observations that M2e shows minimal antigenic variability, even under antibody-mediated pressure in vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body.
Within a living organism.
in vivo adv. , that M2e-specific antibodies typically restrict virus replication in vivo, and that humans exhibit low or undetectable M2e-specific antibody titers provide a strong rationale for further exploration of an M2e-based vaccine.
HA of Influenza A and B Viruses
The HA molecule has a large ectodomain of [approximately equal to] 500 aa. A posttranslational post·trans·la·tion·al
Of or relating to a substance or process, such as the addition of sugar groups to form a glycoprotein, that occurs or is formed after translation of protein: a posttranslational modification. cleavage by host-derived enzymes generates 2 polypeptides that remain linked by a disulfide bond disulfide bond
The covalent bond between sulfur atoms that binds two peptide chains or different parts of one peptide chain and is a structural determinant in many protein molecules. . The larger N-terminal fragment (HA1,320-330 aa) forms a membrane-distal globular globular
resembling a globe.
a spherical cardiac silhouette, usually greatly enlarged and lacking the detailed outline of the right and left atria and apex. Characteristic of pericardial effusion and cardiomyopathy. domain that contains the receptor-binding site and most determinants recognized by virus-neutralizing antibodies. The smaller C-terminal portion (HA2, [approximately equal to] 180 aa, excluding transmembrane transmembrane /trans·mem·brane/ (trans-mem´bran) extending across a membrane, usually referring to a protein subunit that is exposed on both sides of a cell membrane.
adj. and cytoplasmic cytoplasmic
pertaining to or included in cytoplasm.
include secretory inclusions (enzymes, acids, proteins, mucosubstances), nutritive inclusions (glycogen, lipids), pigment granules (melanin, lipofuscin, domain) forms a stemlike structure that anchors the globular domain to the cellular or viral membrane. Sixteen HA subtypes have been identified among influenza A viruses (30); 3 of these (H1, H2, H3) have been associated with classic influenza isolates, and 3 (H5, H7, H9) have been associated with recent sporadic human isolates (1). Influenza B viruses possess only 1 HA subtype.
Although the degree of sequence diversity between subtypes is great, particularly in the HA1 polypeptides (34%-59% homology between subtypes), more conserved regions are found in HA2 (51%-80% homology between subtypes). The most notable region of conservation is the sequence around the cleavage site cleavage site
See restriction site. , particularly the HA2 N-terminal 11 aa, termed fusion peptide, which is conserved among all influenza A subtypes and differs only by 2 conservative aa replacements in influenza B virus. Part of this region is exposed as a surface loop in the HA precursor molecule (HA0) (31). However, when HA0 is cleaved cleaved (klevd) split or separated, as by cutting. into HA1/HA2, the newly generated terminals separate, and the hydrophobic fusion peptide becomes tucked into a cavity of the stem (31). As most HA subtypes are cleaved by extracellular enzymes, this surface loop may be accessible to antibody, at least temporarily, on HA0 expressed in the plasma membrane of infected host cells. The protective potential of antibodies directed to this region of HA0 has been explored in 2 studies by immunization immunization: see immunity; vaccination. of mice with synthetic peptides spanning the cleavage site (32,33). Both studies found that mice vaccinated with a peptide spanning the HA1/HA2 joining region exhibited less illness and fewer deaths on virus challenge (32,33). Most importantly, HA1/HA2 joint-specific antibodies were undetectable in virus-immune human sera (33). These findings make the HA1/HA2 joining region another promising candidate for inclusion in a universal vaccine. Indeed, the authors of 1 study, some of whom had been involved in an M2e-vaccine study, commented that joint-specific immunity in the mouse model was more robust than M2e-specific immunity (33).
Although the HA1/HA2-joining region is the most broadly conserved HA sequence, other determinants on HA2 are shared between a restricted number of subtypes. For instance, a MAb that reduced illness and death in passively immunized mice against viruses of the H 1, H2, and H5 subtypes has been described (34,35). This MAb was shown to recognize a conformational epitope epitope: see immunity. of HA2 (36), but no immunogen that could selectively induce this response has been described. A search for determinants shared by a more restricted number of closely related subtypes such as H2 and H5, which display 85% sequence homology in HA2, or shared by members of the same subtype, which typically display >95% sequence homology in HA2 (30), would be worthwhile, particularly since the HA2-specific antibody response appears to be induced less effectively than the HA1-specific response by infection in humans (37). That many HA2-specific antibodies do not display substantial antiviral activities in vitro does not preclude protective activity in vivo because the mere binding of antibody to native HA expressed on infected cells and infectious virus could mediate protective activity by targeting Fc-receptor expressing cells or complement deposition to these structures.
Other Viral Transmembrane Proteins
To our knowledge, conserved determinants for protective antibodies have not been described for any of the other transmembrane proteins of influenza A and B virus. BM2 of influenza B virus, the homolog hom·o·log
Variant of homologue. of M2, has only a 6-aa-long ectodomain (38). This ectodomain is most likely too small for formation of a BM2-specific epitope because protein epitopes have usually been found to comprise 12-17 contact residues. NB of influenza B virus also shows structural similarities with M2 of influenza A virus, including ion channel ion channel
See channel. activity (39), and has an 18-aa-long ectodomain. However, NB2 has 2 attached carbohydrate chains that can be expected to mask the protein core from recognition by antibody. NA, however, is a good and not sufficiently explored target for cross-protective antibodies. Like HA, it displays a large ectodomain of [approximately equal to] 420 aa. Nine subtypes are recognized among influenza A viruses, while influenza B virus contains 1 subtype. The C-terminal of the polypeptide polypeptide: see peptide. ([approximately equal to] 380 aa) forms a globular head that is anchored to the viral membrane by a flexible stalk. The globular domain contains the enzyme-active site and all known antigenic sites.
Although no cross-protective NA-specific antibody population has been identified, indirect evidence supports the existence of cross-reactive determinants on N1 and N2, the subtypes found in classic human strains. Thus, mice vaccinated first with a mixture of purified N1 and N2 proteins and subsequently boosted with the individual antigens showed a small memory response also against the heterologous heterologous /het·er·ol·o·gous/ (het?er-ol´ah-gus)
1. made up of tissue not normal to the part.
1. subtype (40). Given the ample expression and accessibility of NA on infectious virus and infected host ceils, a search for determinants shared between or within subtypes would be worthwhile.
Studies in animal models have yielded clear evidence for the existence of antibody populations that are directed to relatively invariant determinants of the ectodomains of viral transmembrane proteins and are capable of substantially reducing, in some cases even preventing, clinical illness resulting from influenza virus infection. Additional highly conserved determinants likely exist, particularly on HA2 and NA polypeptides, which can serve as targets for protective antibodies. These targets should be identified for 2 reasons. First, with the exception of the fusion peptide, none of the presently identified "conserved" determinants is totally invariant, and each of these relatively invariant determinants may show increased variability under specific immune pressure. Second, incorporation of several conserved targets in a universal vaccine may decrease the likelihood and rate of emergence of escape mutants and increase the strength of protection.
None of the identified broadly protective antibody populations has been found consistently and at appropriate concentrations in human sera, which indicates that neither is effectively induced by natural
infection or current vaccines. Therefore, the observation that heterosubtypic protection in humans tends to be low does not exclude the possibility of substantial protection by these antibody populations in humans if it can be induced by a specific vaccine. A focused search will likely show additional relatively conserved target structures for protective antibodies. Any of these responses, if not already induced effectively by infection or current vaccines, will be worth pursuing for incorporation into a universal vaccine. The main difficulty may be to develop in each case an immunogenic moiety moiety: see clan. that can effectively induce the desired antibody population. However, even if an appropriate vaccine for induction of a desired broadly protective antibody response cannot be developed, through this research, humanized antibody humanized antibody Molecular medicine A recombinant DNA product which ↓ non-human monoclonal antibody immunogenicity, by transferring the hypervariable genes of rodent antibodies–which encode peptide segments capable of recognizing the desired epitope, reagents may be generated that can be used to treat life-threatening human infections. In view of the potential rewards, the universal vaccine approach should be further explored in animal models and its protective efficacy assessed in humans.
None of the universal vaccines studied thus far in animal models has achieved the level of protection provided with current vaccines. Still, an optimized polyvalent universal vaccine, while not preventing infection, may prevent clinical disease, as has been reported already for 2 vaccination modalities (21,23). If the same results applied to humans, a universal vaccine might replace the current vaccine. Alternatively, if a universal vaccine can only reduce, but not prevent, clinical disease in humans, it could still be used as adjunct to current vaccines and provide increased resistance in case of the unanticipated emergence of a major drift variant or new subtype. Newborns, who are at risk for severe disease, would then receive at least some protection by maternal antibodies. In the elderly, another high-risk population, a universal vaccine may be particularly advantageous because the protective antibodies are generated by memory B cells that tend to be maintained into old age and can be recalled by booster vaccination. In contrast, the efficacy of current inactivated inactivated
rendered inactive; the activity is destroyed.
treated so that they are no longer able to produce evidence of growth or damaging effect on tissue. vaccines depends greatly on the ability to mount a strong response to novel (strain-specific) determinants generated through antigenic drift and shift on HA and NA. This response requires naive B cells, whose frequency tends to decrease with increasing age. When all factors are taken into account, protection against influenza virus infection likely can be improved by a universal vaccine.
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Address for correspondence: Walter Gerhard, Immunology Program, The Wistar Institute, 3601 Spruce St, Philadelphia, PA 19104-4268, USA; fax: 215-898-3868; email: firstname.lastname@example.org.
Walter Gerhard, * Krystyna Mozdzanowska, * and Darya Zharikova *
* The Wistar Institute, Philadelphia, Pennsylvania, USA
Dr Gerhard is a professor in the Immunology Program of the Wistar Institute. He has worked for the past 30 years on issues related to the recognition of and protection against influenza virus by the immune system.