LETTERS

Original Antigenic was enough to render the seasonal actual strain (6). Results from vaccine of the time ineffective, and the a 1984 experiment that used cell cul- Sin and Pandemic new drifted strain was named A′. tures with donor lymphocytes were (H1N1) 2009 Throughout the period, the virus con- similar (7). A 1994 study found that tinued to be the subtype H1N1, as it is current vaccine strains induced anti- To the Editor: While pandemic now designated. bodies to the infl uenza virus circulat- (H1N1) 2009 was in its earliest stages, In 1956, Davenport and Hennessy ing during the childhood of persons age distribution data indicated surpris- examined the responses of 3 in each age cohort (8). An additional ingly few cases among persons >65 different age cohorts, each of which study, published in 2009, confi rmed years of age. The initial assumption received different monovalent infl u- the presence of antigenic sin in mice was that few persons >65 years of enza prepared with vaccine and showed a greater tendency for age had yet to be exposed. However, strains circulating at different earlier live-virus vaccines to produce the phe- as more data became available from periods (3) (Table). Prevaccination se- nomenon (9). Mexico, Australia, and the United rum samples confi rmed the presence One recent study is at variance States, the age distribution pattern of specifi c to the infl uenza with the others. It showed that mono- persisted (1). virus that circulated during each re- clonal antibodies generated through This observation raised the ques- spective cohort’s childhood. were highly specifi c to the tion about whether older persons were Each of the 3 monovalent vac- current vaccine strain rather than to protected from with an infl u- cines was administered to a group infl uenza strains that had circulated in enza virus A (H1N1) strain acquired from each age cohort. Vaccination the past (10). many years ago. Indeed, data from directed toward infl uenza strains dis- At the advent of the 2009 pan- the Centers for Disease Control and tinct from the virus of childhood not demic, fears of a severe pandemic were Prevention showed that approximate- only resulted in development of im- rampant. However, any prior immuni- ly two thirds of older persons have munity to the vaccine strain but also ty that was present in the population evidence of to pandemic boosted the immune response to the would dampen the impact of the virus. (H1N1) 2009 virus. In 1960, Thomas virus strain that circulated during each Early reports confi rmed that the virus Francis proposed the hypothesis of person’s childhood, i.e., original an- was less common in groups of older original antigenic sin, a phenomenon tigenic sin was apparent in each age adults. Vaccine recommendations for whereby a person who as a child was cohort. Several other studies with hu- certain age groups were developed ac- fi rst exposed to a specifi c infl uenza vi- mans, ferrets, rats, and rabbits yielded cording to that pattern of illness. rus A would, throughout life, mount an similar results (4,5). Because infl uenza virus A (H1N1) immune response to the virus of child- Evidence from more recent stud- circulated continually after 1918 until hood, even when exposed to other ies largely supported the veracity of 1957, most persons born before 1957 antigenically dissimilar infl uenza vi- original antigenic sin. In a 1976 study, had been infected primarily with sub- ruses. In effect, the original antibody persons were vaccinated with a virus type H1N1. According to the theory of response generated by the immune that circulated in 1973, an antigeni- original antigenic sin, these persons system against a specifi c infl uenza cally drifted variant of the 1968 infl u- may have partial protection from se- viral strain was hypothesized to have enza virus A (H3N2), and the response vere disease from infection with the colored all future responses to infl u- was assessed. As in earlier studies, ex- new infl uenza virus A (H1N1), i.e., enza (2). amination of the antibodies generated pandemic (H1N1) 2009. Supporting Serologic responses of humans indicated that the vaccine-induced this hypothesis is the paucity of infec- and other mammals have supported antibodies were not only to the 1973 tions in Mexico from persons now in this theory. A new hemagglutinin (HA) variant it contained but also to the vi- their 50s and 60s and few reports in subtype emerged in 1918 that was re- rus that had circulated earlier. As the the United States or Australia of cases sponsible for the pandemic that year. hypothesis postulates, the vaccine- in this age group (1). This fact should Through 1956, the strain evolved, ac- induced antibodies to the 1968 strain inform policy decisions and merits cumulating mutations. In an era before were more numerous than those to the further immunologic consideration. infl uenza were subtyped was performed, the original 1918 infl uenza Table. strains dominant for specific age cohorts from 1956 study* virus A (H1N1) was dubbed a swine Age cohort, y Influenza strain strain, whereas the virus of the 1930s 4–10 (born 1946–1952) Aƍ was known as infl uenza A. However, 17–28 (born 1928–1939) A the amount of drift accrued by 1947 >30 (born <1926) Swine *Adapted from (3).

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Infl uenza surge planning is premised 9. Kim JH, Skountzou I, Compans R, Jacob serial dilution of serum samples was on a high incidence of illness among J. Original antigenic sin responses to infl u- prepared (log ). All virus strains were enza viruses. J Immunol. 2009;183:3294– 4 elderly persons, but if the current pat- 301. DOI: 10.4049/jimmunol.0900398 adjusted to 100 fi fty-percent tissue tern of illness continues, healthcare 10. Wrammert J, Smith K, Miller J. Rapid culture infectious doses. This work- facilities also should prepare to treat cloning of high-affi nity human mono- ing dilution of virus was mixed with younger persons who may constitute clonal antibodies against infl uenza virus. serum dilutions and incubated 1 hour Nature. 2008;453:667–72. DOI: 10.1038/ the bulk of cases. Additionally, stud- nature06890 at 37°C. Madin-Darby bovine kid- ies of persons born during 1957–1968 ney monolayers were infected with should be conducted to quantify anti- Address for correspondence: Amesh A. Adalja, the neutralization mixtures. After 48 body levels to pandemic (H1N1) 2009 Division of Infectious Diseases, University hours of incubation, cells were fi xed virus, focusing on the degree of preex- of Pittsburgh Medical Center, 3601 5th Ave, with acetone (4°C–8°C) and investi- isting immunity that may have existed Ste 300, Pittsburgh, PA 15212, USA; email: gated by indirect immunofl uorescent and was boosted by prior encounters [email protected] assay. Finally, the 50% neutralization with subtype H1N1 viruses titer was calculated. Hyperimmune serum samples Amesh A. Adalja were established by using a 4-fold vac- and D.A. Henderson cination of pigs with of H1N1 Author affi liations: University of Pittsburgh vaccine strains (A/New Jersey/8/1976, Medical Center, Baltimore, Maryland, USA A/sw/Netherlands/25/1980, A/sw/ DOI: 10.3201/eid1606.091563 IDT/Re230/1992, A/sw/Haselünne/ Swine Infl uenza A IDT2617/2003), and a strain of References Vaccines, pandemic (H1N1) 2009 virus (A/ Pandemic (H1N1) Hamburg/7/2009) by using Freund ad- 1. Centers for Disease Control and Preven- juvant. Blood samples were taken 14 tion. Update: novel infl uenza A (H1N1) 2009 Virus, and days after last immunization. A vac- virus —worldwide, May 6, 2009. MMWR Morb Mortal Wkly Rep. Cross-Reactivity cine containing the pandemic (H1N1) 2009;58:453–8. 2009 virus was produced. Swine in- 2. Francis T. On the doctrine of origi- To the Editor: Since its fi rst fl uenza vaccines available in central nal antigenic sin. Proc Am Philos Soc. emergence in the human population in Europe and the newly produced vac- 1960;104:572–8. spring 2009 (1–3) infections with pan- 3. Davenport FM, Hennessy AV. A serologic cine containing pandemic (H1N1) recapitulation of past experiences with in- demic (H1N1) 2009 virus have been 2009 virus (A/Hamburg/7/2009) were fl uenza A; antibody response to monova- reported in pigs, turkeys, and some administered to pigs (2-fold vaccina- lent vaccine. J Exp Med. 1956;104:85–97. carnivore species (4,5). The pandemic tion with 1–2 mL of the vaccine 21–28 DOI: 10.1084/jem.104.1.85 (H1N1) 2009 virus can be experimen- 4. Fazekas de St Groth B, Webster RG. days apart intramuscularly). Blood Disquisitions on original antigenic tally transmitted between pigs (6). was withdrawn 7 days after second sin. II. Proof in lower creatures. J Exp The reported transmissibility of the administration. Med. 1966;121:347–61. DOI: 10.1084/ virus raises the question as to whether In addition, an experimental aero- jem.124.3.347 authorized swine infl uenza vaccine 5. Fazekas de St Groth B, Webster RG. Dis- sol infection was conducted by using quisitions on original antigenic sin. I. Evi- strains may be cross-reactive to pan- the parental strain of the most recent dence in man. J Exp Med. 1966;121:331– demic (H1N1) 2009 virus. Kyriakis et avH1N1 strain contained in a Euro- 45. DOI: 10.1084/jem.124.3.331 al. (7) investigated the cross-reactivity pean swine infl uenza vaccine (A/sw/ 6. Webster RG, Kasel JA, Couch RB, Laver of 66 pig serum samples from differ- WG. Infl uenza virus subunit vaccines. II. Haselünne/IDT2617/2003). Blood Immunogenicity and original antigenic sin ent infection and vaccination trials and samples were taken 10 days after in- in humans. J Infect Dis. 1976;134:48–58. reported cross-reactions between the fection. 7. Yarchoan R, Nelson DL. Specifi city of in avian-like H1N1 viruses circulating in The investigation of the hyper- vitro anti-infl uenza virus antibody produc- the European pig population (avH1N1) tion by human lymphocytes: analysis of immune serum samples detected original antigenic sin by limiting dilution and the classical swine H1N1 viruses neutralizing activity between the cultures. J Immunol. 1984;132:928–35. (cH1N1) with pandemic (H1N1) 2009 pandemic (H1N1) 2009 virus and 8. Powers DC, Belshe RB. Vaccine-induced virus by hemagglutination inhibition European avH1N1 vaccine strains antibodies to heterologous infl uenza assay. A H1N1 viruses: effects of again and (A/sw/Netherlands/25/1980, A/sw/ “original antigenic sin.” J Infect Dis. To investigate this cross-reactivity IDT/Re230/1992, A/sw/Haselünne/ 1994;169:1125–9. in more detail, a neutralization test was IDT2617/2003), as well as with the applied in the study we report here. A cH1N1 strain A/New Jersey/8/1976

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