GENOMICS AND DRUG RESPONSE
Am J Pharmacogenomics 2004; 4 (5): 293-298 1175-2203/04/0005-0293/$31.00/0 © 2004 Adis Data Information BV. All rights reserved.
Human Genetics and Responses to Influenza Vaccination Clinical Implications Robert Lambkin,1 Patricia Novelli,1 John Oxford1 and Colin Gelder2 1 2
Department of Medical Microbiology and Retroscreen Virology, Queen Mary’s School of Medicine and Dentistry, London, England University of Wales College of Medicine, Heath Park, Cardiff, Wales
Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 1. Human Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 2. Defense Against Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 3. Virus Host Interactions During Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 4. Influenza Vaccines and Current Vaccination Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 5. Non-Responsiveness to Influenza Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 5.1 Previous Exposure to Vaccine Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 5.2 Age and Immune Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 5.3 Genetic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
Abstract
Influenza A and B viruses are negative-strand RNA viruses that cause regular outbreaks of respiratory disease and substantially impact on morbidity and mortality. Our primary defense against the influenza virus infection is provided by neutralizing antibodies that inhibit the function of the virus surface coat proteins hemagglutinin and neuraminidase. Production of these antibodies by B lymphocytes requires help from CD4+ T cells. The most commonly used vaccines against the influenza virus comprise purified preparations of hemagglutinin and neuraminidase, and are designed to induce a protective neutralizing antibody response. Because of regular antigenic change in these proteins (drift and shift mutation), the vaccines have to be administered on an annual basis. Current defense strategies center on prophylactic vaccination of those individuals who are considered to be most at risk from the serious complications of infection (principally individuals aged >65 years and those with chronic respiratory, cardiac, or metabolic disease). The clinical effectiveness of influenza virus vaccination is dependent on several vaccine-related factors, including the quantity of hemagglutinin within the vaccine, the number of doses administered, and the route of immunization. In addition, the immunocompetence of the recipient, their previous exposure to influenza virus and influenza virus vaccines, and the closeness of the match between the vaccine and circulating influenza virus strains, all influence the serologic response to vaccination. However, even when these vaccines are administered to young fit adults a proportion of individuals do not mount a significant serologic response to the vaccine. It is not clear whether these nonresponding individuals are genetically pre-programmed to be nonresponders or whether failure to respond to the vaccine is a random event. There is good evidence that nonresponsiveness to hepatitis B vaccine, another purified protein vaccine, is at least partially modulated by an individual’s human leucocyte antigen (HLA) alleles. Because CD4+ T cells, which control the neutralizing antibody response to influenza virus, recognize antigens in association with HLA class II
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molecules, we recently conducted a small study to investigate whether there was any association between HLA class II molecules and nonresponsiveness to influenza virus vaccination. This work revealed that the HLA-DRB1*0701 allele was over represented among persons who fail to mount a neutralizing antibody response. This preliminary finding is important because it potentially identifies a group who may not be protected by current vaccination strategies. Further investigation into the role of HLA polymorphisms and nonresponse to influenza virus vaccination, and vaccination against viruses in general, is clearly required.
The Gauguin painting “Where do we come from; What are we; Where are we going” emphasized the major scientific and philosophical questions of the last century.[1] The intense analysis of the human genome that is the focus of modern medicine now encourages such precise questions as: What is the genetic basis to allow a micro-organism to invade and kill one person while his neighbor escapes unharmed? This paradox is nowhere more exemplified than in the great influenza virus pandemic of 1918. It is now estimated that over 50 million persons died in that pandemic.[2] Nevertheless, in most countries 95% of persons infected with the virus survived. The virulence of the virus may be explained by the analyses of its eight genes, and we have proceeded to uncover clinical material from permafrost burials and pathology museum paraffin blocks from the lungs of persons who died from the influenza virus in 1918.[3] However, to date, with half the genome aligned, there is no clear indication of why this particular pandemic influenza virus was so virulent.[4] Of course the innate and pre-programmed immune system will form the main initial protection against any influenza virus and an immune memory from previous outbreaks may give protection or, unusually, may actually enhance the disease’s virulence. There is a strong link at the operational level between an individual’s immune response and that person’s genetic disposition. In the present review we will analyze the genetic basis of this link, with particular reference to how the genes of the human leucocyte antigen (HLA) complex may modulate the antibody response to influenza virus hemagglutinin, a key defense against infection. 1. Human Influenza Influenza A and B viruses are negative-strand RNA viruses. In humans these viruses attack the respiratory tract (nose, throat, and lungs) resulting in a wide range of respiratory (dry cough, sore throat, nasal congestion) and systemic (fever, headache, muscle and joint aches, shivering, and general fatigue) symptoms. During a typical outbreak of influenza virus 10–20% of the population develop serologic evidence of infection.[5] In young healthy adults the majority of these infections are resolved within 1 week, but in a minority the virus is associated with complications, such as bronchitis, pneumonia, and cardiac failure, which may become lifethreatening. Those most at risk are infants (aged between 6 and 23 © 2004 Adis Data Information BV. All rights reserved.
months old),[6,7] people aged over 65 years of age, individuals of all ages who have chronic respiratory, cardiac, metabolic (particularly diabetes) or immune system disorders,[8] women in their second or third trimesters of pregnancy,[9] and those in residential or institutional care.[10] Influenza virus infection has a substantial impact on mortality rates. In the US during an influenza virus epidemic it has been estimated that 300 000 people will be hospitalized and 25 000 will die.[11] Ninety-five percent of deaths related to influenza virus (in non-pandemic years) occur in those over the age of 65 years or in the at-risk groups.[6] 2. Defense Against Influenza Antibodies are considered to be our primary defense against influenza virus infection, especially ‘neutralizing antibodies’ which inhibit the function of the viral surface coat proteins hemagglutinin and neuraminidase.[12] Probably as a result of selection pressure by neutralizing antibodies, the virus undergoes continual small changes in its antigenic structure (antigenic drift) which lead to the regular seasonal outbreaks and influenza virus epidemics. Less frequently, influenza virus pandemics occur which result from large changes in the virus antigenic structure (antigenic shift). The production of neutralizing antibodies is under the control of CD4+ T cells,[5,13,14] which recognize antigen in association with HLA class II molecules. In contrast to the strain-specific protection provided by neutralizing antibodies, the cell-mediated immune response to influenza virus is cross-reactive between different serological subtypes,[15] though, while an early T-cell cytotoxic response may reduce the intensity of the infection, this response is primarily believed to be involved in viral clearance and recovery from established infection.[16] 3. Virus Host Interactions During Infection During influenza virus infection large numbers of cells in the respiratory tract will be programmed by the virus to produce up to 10 000 daughter virions which then rapidly infect other host cells. Exactly which of the 30 000 active human genes are modulated by the virus during this 8 hour infection process is largely unknown, Am J Pharmacogenomics 2004; 4 (5)
Human Genetics and Responses to Influenza Vaccination
though it is well recognized that the presence of double-stranded viral RNA (dsRNA), which is required as an intermediate for viral replication, triggers several signaling pathways with the cell.[17] In particular, dsRNA activates pathways that regulate the type I interferon (IFN) response and the expression of antiviral cytokines, including the IκB kinase-nuclear factor-κB (IKK-NF) pathway, and both the c-Jun N-terminal kinase (JNK) and the p38 MAP kinase (MAPK) cascades.[18] Interestingly, a major in vivo function of the influenza virus RNA-binding non-structural protein-1 (NS1) is to antagonize the antiviral type-I IFN system.[19] NS1 inhibits activation of the gene encoding IFNβ (IFNB1), which is controlled by the transcriptional activators NF-κB, IFN regulatory factor-3 (IRF3) and activating transcription factor 2 (ATF-2)/cJun.[20-22] However, it was noted more than 20 years ago that influenza virus strains differ in their ability to induce IFNα and IFNβ, and this correlates with their individual neuraminidase activity rather than their NS1 activity.[23] In a subsequent study, neuraminidase was shown to convert transforming growth factor-β (TGFβ) from the latent to the active form to an extent sufficient to induce TGFβ-dependent apoptosis.[24] The other viral surface coat protein, hemagglutinin, can also stimulate signaling pathways from both inside and outside the cell: binding of recombinant hemagglutinin to cell surface receptors leads to a rapid induction of protein kinase C (PKC) signaling, whereas over-expression of hemagglutinin inside the cell leads to the activation of NFκB.[14,25,26] 4. Influenza Vaccines and Current Vaccination Strategies Inactivated influenza virus vaccines are generally poor at boosting the cytotoxic T-cell responses[27] and principally function by inducing anti-hemagglutinin and anti-neuraminidase antibodies. The clinical effectiveness of influenza virus vaccination is dependent on the immunocompetence of the recipient, their previous exposure to influenza virus and influenza virus vaccines, and the closeness of the match between the vaccine and circulating influenza virus strains.[28] Production of these antibodies is under the control of CD4+ T cells. Vaccines contain two influenza virus A strains (H3N2, and H1N1 subtypes) and an influenza B virus. The most commonly used preparations are trivalent inactivated influenza virus vaccines cultured in the allantoic fluid of embryonated chicken eggs, chemically inactivated with either β-propiolactone or formaldehyde, and then disrupted with detergents to yield membrane fragments containing the surface antigenic hemagglutinin and neuraminidase proteins. Influenza virus vaccination campaigns usually target at-risk groups.[28] Because of antigenic shift and drift, vaccines have to be © 2004 Adis Data Information BV. All rights reserved.
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continually updated and administered on an annual basis. When the match between the vaccine and circulating strains is good, protection rates of up to 90% occur in young fit adults.[29] Vaccination has been shown to reduce mortality in those over 55 years old in an at-risk group by 90%,[30] and in the elderly by 45%.[31] In addition, vaccination of the elderly population reduces hospital admissions for influenza by 50%,[32] and is highly cost effective.[28] However, despite the clear benefits of vaccination, influenza virus still occurs in 30–50% of this age group during an outbreak. Given the huge health burden of the influenza virus, and the ever-present threat of a future pandemic,[33] immunologic failure to mount an anti-hemagglutinin antibody response is an significant public health issue which has led to considerable efforts to improve influenza virus vaccines. 5. Non-Responsiveness to Influenza Vaccine The concept of nonresponsiveness to a vaccine has been exemplified with hepatitis B vaccine where, in extremis, 18 or more doses are required in some individuals to induce an immune response that in most recipients requires only two or three vaccinations. A variety of factors have been linked to poor or nonresponse to influenza virus vaccination. 5.1 Previous Exposure to Vaccine Components
The serologic response to a vaccine is determined by several factors, including the quantity of hemagglutinin within the vaccine,[34] the number of doses administered,[35] and the route of immunization.[36] While it is also theoretically possible that differences in glycosylation between egg-derived influenza virus vaccines strains and wild-type human influenza viruses might modulate serologic responses to vaccination, we have found only modest improvements in antibody response to vaccination when previous nonresponders to a conventional egg-derived vaccine were re-vaccinated with Madin-Darby canine kidney cell (MDCK)-derived preparations.[37] Previous exposure to the vaccine components, the concept of ‘original antigenic sin’, has also been proposed as an explanation for the differences in antibody response.[38-40] It is thought that antibodies from previous exposures may interfere with the formation of antibodies against the vaccine strain because B cells primed to respond to the original antigen will respond to the vaccine before a primary response to the modified virus can be initiated.[41,42] 5.2 Age and Immune Status
The age and immune status of the vaccine recipient is an important consideration in responsiveness to vaccination. Elderly individuals generally produce significantly lower antibody titers Am J Pharmacogenomics 2004; 4 (5)
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Table I. Frequency of human leukocyte antigen (HLA) alleles in responders versus nonresponders to influenza vaccination HLA allele
Frequency in responders (n = 41) [%]
Frequency in nonresponders (n = 32) [%]
p-Value
Odds ratioa
HLA-DRB1*0701
14.6
40.6
0.016
4.0
HLA-DQB1*0603-9/14
34.1
9.4
0.005
0.12
a
Fisher’s Exact test.
following influenza virus vaccination when compared with young adults.[43] Speculation has centered on age-related differences at the helper T-cell level. Although a negative correlation between naive helper T-cell numbers and a positive correlation for memory helper T-cell numbers and vaccine response was observed in some strains of virus/vaccine studied, this did not explain the lower antibody response observed in the other strains.[44] The elderly may produce anti-hemagglutinin antibodies to related H1N1 strains when vaccinated, rather than those strains contained within the vaccine, presumably due to ‘original antigenic sin’.[45] This effect was not seen, however, for the H3N2 component. In addition, the generally accepted surrogate marker for protection, a reciprocal hemaggluination inhibition titer greater than 40,[46] may not be as reliable in the elderly population.[43] In contrast, levels of serum cytokines have been shown not to be different among elderly responders and nonresponders to influenza virus vaccination.[47] 5.3 Genetic Factors
Host genetic factors might modulate the antibody response to influenza virus vaccination. As noted above, influenza virus vaccination is rarely, if ever, universally protective. In most trials a proportion of individuals fail to respond to the vaccine. The key question here is whether these individuals are genetically preprogrammed to be nonresponders or whether failure to respond to the vaccine is a random event. Researchers in the 1970s investigated the effect of ABO blood groups on susceptibility to infection; however, the results were inconclusive.[48] In the 1990s, the MxA and MxB IFN-induced proteins were implicated in protection against influenza virus infection, particularly in the mouse transfection models.[49] The human myxovirus (influenza virus) resistance 1 (MX1) gene (encoding MxA) is located on chromosome 21, yet individuals with trisomy of this chromosome, who might, therefore, be expected to have increased levels of MxA expression, display increased susceptibility to upper respiratory infections when compared with controls.[50] Because there is good evidence that nonresponsiveness to the hepatitis B vaccine is, at least partially, modulated by an individuals HLA alleles,[51-53] we recently investigated whether there was © 2004 Adis Data Information BV. All rights reserved.
any association between HLA class II molecules and nonresponsiveness to influenza virus vaccination.[54] This study investigated a cohort of 73 unrelated Caucasoid adults who were are at risk for influenza virus. An increased frequency of HLA-DRB1*0701 and a decreased frequency of HLA-DQB1*0603-9/14 was found in those who failed to respond to the influenza virus subunit vaccine, when compared with matched responders to the same vaccine (see table I). The finding that the HLA-DRB1*0701 allele is overrepresented among persons who fail to mount a neutralizing antibody response to influenza virus is important because it potentially identifies a group who may not be protected by current vaccination strategies. There are several potential mechanisms by which HLA class II genes might modulate antibody responses to subunit vaccines. Firstly, the defect might be in the presentation of appropriate antigens to CD4+ T cells; thus, persons who carry HLADRB1*0701 may fail to recognize peptide epitopes exhibited by the subunit vaccines, either because suitable epitopes are not appropriately processed, or because the processed peptides are unable to bind to appropriate HLA class II molecules. By the same mechanism, HLA-DQB1*0603-9/14 (which was associated with responsiveness) may be particularly efficient at the processing and/or presentation of these antigens. However, we have previously investigated CD4+ T-cell recognition of influenza virus A/ Beijing/32/92 (H3N2) hemagglutinin following both natural infection[55] and subunit vaccinations[56] and found that HLA-DRB1*07 can bind synthetic peptides spanning the sequence of this hemagglutinin and that HLA-DRB1*07-restricted CD4+ lymphocytes can recognize and proliferate appropriately in response to these peptides at least in vitro.[57] A second explanation for the lack of an hemagglutinin antibody response is that nonresponsiveness is a more general phenomenon relating to CD4+ T cell-derived help for B cells that is necessary for antibody production. The nature of such a defect is unclear, but it is compelling in that HLA-DRB1*0701 has also been associated with low responses to the hepatitis B vaccine.[51,52] Thus, it is conceivable that persons with the HLA-DRB1*0701 allele may have a more general defect in antibody responses to soluble antigens. It will be important to determine whether nonresponders to influenza virus vaccine respond normally to other vaccines (inAm J Pharmacogenomics 2004; 4 (5)
Human Genetics and Responses to Influenza Vaccination
cluding whole-virus preparations and live vaccines). Because a significant minority of donors with the HLA-DRB1*0701 allele mount a normal antibody response to influenza virus vaccine, we believe that the deficit is likely to be in a gene linked to HLADRB1*0701 rather than in the DRB1*0701 allele itself. 6. Conclusions The observation that HLA class II alleles modulate the serologic response to influenza virus vaccination is important, but further investigations are clearly required to confirm these findings. It is also very likely that polymorphisms in other genes also modulate the antibody response to influenza virus vaccination. It will be interesting to discover if the same sets of genes modulate the immunologic response to natural infection. As precise data are now becoming available on the human gene sets that are transcribed (or alternatively down-regulated) during influenza virus infection, it may soon be possible to answer this question. In the interim, we would recommend that future vaccination strategies should encompass the potential for genetic differences in antibody response to influenza virus vaccines. Acknowledgments The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.
References 1. Klein T, Kakahata N. Where do we come from: the molecular evidence for human descent. Berlin: Springer, 2002: 462 2. Oxford J. Influenza A pandemics in the 20th century with special reference to 1918: virology, pahtology and epidemiology. Rev Med Virol 2002; 10: 119-33 3. Reid A, Janczewski TA, Lourens RM, et al. 1918 influenza pandemic caused by highly conserved viruses with two receptor-binding variants. Emerg Infect Dis 2003 Oct; 9 (10): 1249-53 4. Basler CF, Reid AH, Dybing JK, et al. Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. Proc Natl Acad Sci U S A 2001; 98 (5): 2746-51 5. Nicholson KG. Clinical features of influenza. Semin Respir Infect 1992; 7 (1): 26-37 6. Sprenger MJ, Van Naelten MA, Mulder PG, et al. Influenza mortality and excess deaths in the elderly, 1967-82. Epidemiol Infect 1989; 103 (3): 633-41 7. Sprenger MJ, Mulder PG, Beyer WE, et al. Impact of influenza on mortality in relation to age and underlying disease, 1967-1989. Int J Epidemiol 1993; 22 (2): 334-40 8. Barker W, Mullooly JP. Pneumonia and influenza deaths during epidemics: implications for prevention. Arch Intern Med 1982; 142: 85-9 9. Irving WL, James DK, Stephenson T, et al. Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study. Br J Obstet Gynecol 2000; 107 (10): 1282-9 10. Fedson DS. Prevention and control of influenza in institutional settings. Hosp Pract (Off Ed) 1989; 24 (9A): 87-96 11. Simonsen L, Clarke MJ, Stroup DF, et al. A method for timely assessment of influenza-associated mortality in the United States. Epidemiology 1997; 8 (4): 390-5 12. Potter JM, Oxford J. Determinants of immunity to influenza infection in man. Br Med Bull 1979; 35: 45-69 © 2004 Adis Data Information BV. All rights reserved.
297
13. Anders EM, Peppard PM, Burns WH, et al. In vitro antibody response to influenza virus: I. T cell dependence of secondary response to hemagglutinin. J Immunol 1979; 123 (3): 1356-61 14. Callard RE, Smith CM. Histocompatibility requirements for T cell help in specific in vitro antibody responses to influenza virus by human blood lymphocytes. Eur J Immunol 1981; 11 (3): 206-12 15. McMichael AJ, Askonas BA. Influenza virus-specific cytotoxic T cells in man: induction and properties of the cytotoxic cell. Eur J Immunol 1978; 8 (10): 705-11 16. McMichael AJ, Gotch FM, Noble GR, et al. Cytotoxic T-cell immunity to influenza. N Engl J Med 1983; 309 (1): 13-7 17. Maide JA. Viral double-stranded RNA, cytokines and the flu. J Interferon Cytokine Res 2002; 20: 250-72 18. Kujime K, Hashimoto S, Gon Y, et al. p38 mitogen-activated protein kinase and cjun-NH2-terminal kinase regulate RANTES production by influenza virusinfected human bronchial epithelial cells. J Immunol 2000; 164 (6): 3222-8 19. Garcia-Sastre A. Inhibition of intereferon-mediated antiviral responses by influenza A viruses and other negative strand RNA viruses. Virology 2001; 279: 375-84 20. Ludwig S, Wang X, Ehrhardt C, et al. The influenza A virus NS1 protein inhibits activation of Jun N-terminal kinase and AP-1 transcription factors. J Virol 2002; 76 (21): 11166-71 21. Wang X, Li M, Zheng H, et al. Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon. J Virol 2000; 74 (24): 11566-73 22. Talon J, Horvath CM, Polley R, et al. Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J Virol 2000; 74 (17): 7989-96 23. Chamik M. Interferon induction by influenza virus: significance of neuraminidase. Arch Immunol Ther Exp 1981; 29: 109-14 24. Schultz-Cherry S, Hinshaw V. Influenza virus neuraminidase activates latent transforming growth factor beta. J Virol 1996; 70: 8624-9 25. Rott O, Charreire J, Semichon M, et al. B cell superstimulatory influenza virus (H2-subtype) induces B cell proliferation by a PKC-activating, Ca (2+)-independent mechanism. J Immunol 1995; 154 (5): 2092-103 26. Flory E, Kunz M, Scheller C, et al. Influenza virus-induced NF-κB-dependent gene expression is mediated by overexpression of viral proteins and involves oxidative radicals and activation of IκB kinase. J Biol Chem 2000; 275 (12): 8307-14 27. McMichael AJ, Gotch F, Cullen P, et al. The human cytotoxic T cell response to influenza A vaccination. Clin Exp Immunol 1981; 43 (2): 276-84 28. Bridges CB, Fukuda K, Cox NJ, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2001; 50 (RR-4): 1-44 29. Nichol KL. Cost-benefit analysis of a strategy to vaccinate healthy working adults against influenza. Arch Intern Med 2001; 161 (5): 749-59 30. Fleming DM, Watson JM, Nicholas S, et al. Study of the effectiveness of influenza vaccination in the elderly in the epidemic of 1989-90 using a general practice database. Epidemiol Infect 1995; 115 (3): 581-9 31. Nichol KL, Baken L, Wuorenma J, et al. The health and economic benefits associated with pneumococcal vaccination of elderly persons with chronic lung disease. Arch Intern Med 1999; 159 (20): 2437-42 32. Nichol KL, Margolis KL, Wouremna J, et al. Effectiveness of influenza vaccine in the elderly. Gerontology 1996; 42 (5): 274-9 33. Dowdle WR. Influenza pandemics: lessons for the future [letter]. Vaccine 2002; 20 Suppl. 2: S15 34. Mostow SR, Schoenbaum SC, Dowdle WR, et al. Studies on inactivated influenza vaccines: II. Effect of increasing dosage on antibody response and adverse reactions in man. Am J Epidemiol 1970; 92 (4): 248-56 35. Holland W, Isaacs A, Clarke S, et al. A serological trial of Asian influenza vaccine after the autumn epidemic. Lancet 1958; I (7025): 820-2 36. Stuart-Harris C, Schild GC, Oxford J. Influenza: the viruses and the disease. 2nd ed. London: Edward Arnold, 1985: 118-38 37. Oxford J, Al-Jabri A, Lambkin R, et al. Non-responders to egg grown influenza vaccine seroconvert after booster immunization with MDCK cell grown vaccine. Vaccine 2003 Jun 20; 21 (21-22): 2743-6 38. Fazekas de St Groth B, Webster RG. Disquisitions of original antigenic sin: I. Evidence in man. J Exp Med 1966; 124 (3): 331-45 Am J Pharmacogenomics 2004; 4 (5)
298
Lambkin et al.
39. Fazekas de St Groth B, Webster RG. Disquisitions on original antigenic sin: II. Proof in lower creatures. J Exp Med 1966; 124 (3): 347-61
50. Horisberger MA. Interferons, Mx genes, and resistance to influenza virus. Am J Respir Crit Care Med 1995; 152 (4 Pt 2): S67-71
40. Webster RG. Original antigenic sin in ferrets: the response to sequential infections with influenza viruses. J Immunol 1966; 97 (2): 177-83
51. Alper CA, Kruskall MS, Marcus-Bagley D, et al. Genetic prediction of nonresponse to hepatitis B vaccine. N Engl J Med 1989; 321 (11): 708-12
41. McElhaney JE, Meneilly GS, Lechelt KE, et al. Antibody response to whole-virus and split-virus influenza vaccines in successful ageing. Vaccine 1993; 11 (10): 1055-60
52. McDermott AB, Zuckerman JN, Sabin CA, et al. Contribution of human leukocyte antigens to the antibody response to hepatitis B vaccination. Tissue Antigens 1997; 50 (1): 8-14
42. Powers DC, Belshe RB. Effect of age on cytotoxic T lymphocyte memory as well as serum and local antibody responses elicited by inactivated influenza virus vaccine. J Infect Dis 1993; 167 (3): 584-92
53. Desombere I, Willems A, Leroux-Roels G. Response to hepatitis B vaccine: multiple HLA genes are involved. Tissue Antigens 1998; 51 (6): 593-604
43. Murasko DM, Bernstein ED, Gardner EM, et al. Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly. Exp Gerontol 2002; 37 (2-3): 427-39
54. Gelder CM, Lambkin R, Hart KW, et al. Associations between human leukocyte antigens and nonresponsiveness to influenza vaccine. J Infect Dis 2002; 185 (1): 114-7
44. Remarque EJ, Cools HJ, Boere TJ, et al. Functional disability and antibody response to influenza vaccine in elderly patients in a Dutch nursing home. BMJ 1996; 312 (7037): 1015
55. Gelder CM, Welsh KI, Faith A, et al. Human CD4+ T-cell repertoire of responses to influenza A virus hemagglutinin after recent natural infection. J Virol 1995; 69 (12): 7497-506
45. Remarque EJ, de Bruijn IA, Boersma WJ, et al. Altered antibody response to influenza H1N1 vaccine in healthy elderly people as determined by HI, ELISA, and neutralization assay. J Med Virol 1998; 55 (1): 82-7
56. Gelder CM, Lamb JR, Askonas BA. Human CD4+ T-cell recognition of influenza A virus hemagglutinin after subunit vaccination. J Virol 1996; 70 (7): 4787-90
46. Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutinationinhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg (Lond) 1972; 70 (4): 767-77
57. Gelder C, Davenport M, Barnardo M, et al. Six unrelated HLA-DR-matched adults recognize identical CD4+ T cell epitopes from influenza A haemagglutinin that are not simply peptides with high HLA-DR binding affinities. Int Immunol 1998; 10 (2): 211-22
47. Krakauer T, Russo C. Serum cytokine levels and antibody response to influenza vaccine in the elderly. Immunopharmacol Immunotoxicol 2001; 23 (1): 35-41 48. Mackenzie JS, Fimmel PJ. The effect of ABO blood groups on the incidence of epidemic influenza and on the response to live attenuated and detergent split influenza virus vaccines. J Hyg (Lond) 1978; 80 (1): 21-30 49. Pavlovic J, Zurcher T, Haller O, et al. Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. J Virol 1990; 64 (7): 3370-5
© 2004 Adis Data Information BV. All rights reserved.
Correspondence and offprints: Dr Robert Lambkin, Department of Medical Microbiology and Retroscreen Virology, Queen Mary’s School of Medicine and Dentistry, St Bart’s and the London, 327 Mile End Road, London, E1 4NS, UK. E-mail:
[email protected]
Am J Pharmacogenomics 2004; 4 (5)
