Original antigenic sin responses to influenza viruses.
ABSTRACT Most immune responses follow Burnet's rule in that Ag recruits specific lymphocytes from a large repertoire and induces them to proliferate and differentiate into effector cells. However, the phenomenon of "original antigenic sin" stands out as a paradox to Burnet's rule of B cell engagement. Humans, upon infection with a novel influenza strain, produce Abs against older viral strains at the expense of responses to novel, protective antigenic determinants. This exacerbates the severity of the current infection. This blind spot of the immune system and the redirection of responses to the "original Ag" rather than to novel epitopes were described fifty years ago. Recent reports have questioned the existence of this phenomenon. Hence, we revisited this issue to determine the extent to which original antigenic sin is induced by variant influenza viruses. Using two related strains of influenza A virus, we show that original antigenic sin leads to a significant decrease in development of protective immunity and recall responses to the second virus. In addition, we show that sequential infection of mice with two live influenza virus strains leads to almost exclusive Ab responses to the first viral strain, suggesting that original antigenic sin could be a potential strategy by which variant influenza viruses subvert the immune system.
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ABSTRACT: Influenza viruses typically cause the most severe disease in children and elderly individuals. However, H1N1 viruses disproportionately affected middle-aged adults during the 2013-2014 influenza season. Although H1N1 viruses recently acquired several mutations in the hemagglutinin (HA) glycoprotein, classic serological tests used by surveillance laboratories indicate that these mutations do not change antigenic properties of the virus. Here, we show that one of these mutations is located in a region of HA targeted by antibodies elicited in many middle-aged adults. We find that over 42% of individuals born between 1965 and 1979 possess antibodies that recognize this region of HA. Our findings offer a possible antigenic explanation of why middle-aged adults were highly susceptible to H1N1 viruses during the 2013-2014 influenza season. Our data further suggest that a drifted H1N1 strain should be included in future influenza vaccines to potentially reduce morbidity and mortality in this age group.Proceedings of the National Academy of Sciences 10/2014; · 9.81 Impact Factor
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ABSTRACT: Background. Recent studies suggest that influenza vaccination in the previous season may influence the effec-tiveness of current-season vaccination, but this has not been assessed in a single population over multiple years. Methods. Patients presenting with acute respiratory illness were prospectively enrolled during the 2004–2005 through 2012–2013 influenza seasons. Respiratory swabs were tested for influenza and vaccination dates obtained from a validated registry. Vaccination status was determined for the current, previous, and prior 5 seasons. Vaccine effectiveness (VE) was calculated for participants aged ≥9 years using logistic regression models with an interaction term for vaccination history. Results. There were 7315 enrollments during 8 seasons; 1056 (14%) and 650 (9%) were positive for influenza A (H3N2) and B, respectively. Vaccination during current only, previous only, or both seasons yielded similar protec-tion against H3N2 (adjusted VE range, 31%–36%) and B (52%–66%). In the analysis using 5 years of historical vac-cination data, current season VE against H3N2 was significantly higher among vaccinated individuals with no prior vaccination history (65%; 95% confidence interval [CI], 36%–80%) compared with vaccinated individuals with a frequent vaccination history (24%; 95% CI, 3%–41%; P = .01). VE against B was 75% (95% CI, 50%–87%) and 48% (95% CI, 29%–62%), respectively (P = .05). Similar findings were observed when analysis was restricted to adults 18–49 years. Conclusions. Current-and previous-season vaccination generated similar levels of protection, and vaccine-induced protection was greatest for individuals not vaccinated during the prior 5 years. Additional studies are needed to understand the long-term effects of annual vaccination. Keywords. influenza; vaccine effectiveness. The Advisory Committee on Immunization Practices (ACIP) has recommended annual influenza vaccina-tions for all persons aged ≥6 months since 2010 . Although annual vaccination has been recommended for adults aged ≥65 years and certain high-risk groups for decades, the impact of prior vaccination history on current-season vaccine effectiveness (VE) is unclear. Despite previous debates on the relevance of repeated vaccination [2, 3], few influenza VE studies have consid-ered the effect of vaccinations received in prior seasons. In the 1980s, a multiseason randomized, placebo-controlled trial among healthy adults found no con-sistent differences in efficacy of primary vs repeated vaccination against serologically confirmed influenza [4, 5]. Recent observational studies have suggested that VE may be influenced by prior season vaccination [6–12]. However, these studies were limited to 1 or 2 seasons,Clinical Infectious Diseases 09/2014; 54449. · 9.42 Impact Factor
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ABSTRACT: Influenza is a perennial problem affecting millions of people annually with the everpresent threat of devastating pandemics. Active prophylaxis by vaccination against influenza virus is currently the main countermeasure supplemented with antivirals. However, disadvantages of this strategy include the impact of antigenic drift, necessitating constant updating of vaccine strain composition, and emerging antiviral drug resistance. The development of other options for influenza prophylaxis, particularly with broad acting agents able to provide protection in the period between the onset of a pandemic and the development of a strain specific vaccine, is of great interest. Exploitation of broad-spectrum mediators could provide barricade protection in the early critical phase of influenza virus outbreaks. Passive immunity has the potential to provide immediate antiviral effects, inhibiting virus replication, reducing virus shedding, and thereby protecting vulnerable populations in the event of an impending influenza pandemic. Here, we review passive broad-spectrum influenza prophylaxis options with a focus on harnessing natural host defenses, including interferons and antibodies.Influenza research and treatment. 01/2014; 2014:267594.