doi: 10.1093/infdis/jiy443. from subjects at 4 to 12?years old during the year of initial virus isolation, except the age-independent anti-HA antibody response against A(H1N1)pdm09 viruses. More participants possessed antibodies Loratadine that reacted to multiple antigenically distinct NA proteins than those with antibodies that reacted to multiple antigenically distinct HA proteins. Our results support the need to include NA proteins in seasonal influenza vaccine preparations. KEYWORDS: influenza, imprinting, neuraminidase, hemagglutinin, antigenic drift INTRODUCTION Influenza viruses continue to pose significant morbidity, mortality, and socioeconomic burden worldwide as antigenic variants that evade preexisting immunity continuously emerge, causing regular epidemics and infrequent pandemics. The most administered inactivated influenza vaccines induce neutralizing antibodies targeting the receptor-binding domain of the main surface glycoprotein, hemagglutinin (HA), and this strategy is supported by the establishment of the HA inhibition (HI) antibodies as a key correlate of protection (1). Other serological correlates of protection, such as HA-stalk reactive antibodies (2, 3) and anti-neuraminidase (NA) antibodies (4, 5), have been identified more recently through observational and human Loratadine challenge studies. Specifically, anti-NA antibodies have been reported to protect against infection, reduce symptoms, and/or shorten the duration of viral shedding (2,C7). Individual and population immunity are continuously shaped by influenza virus antigenic drifts and shifts. During primary exposure to the influenza virus, memory B cells are developed to react to a range of conserved and nonconserved viral epitopes. These memory B cells may bias future antibody responses upon exposure to an antigenic variant in a phenomenon referred to as immune imprinting. Immune response to a subsequent infection or vaccination is thus influenced by the antigenic similarity of later strains to an individuals initial exposure. Experimental and observational studies have identified immune imprinting as an important driver of the anti-HA antibody immune landscape with both beneficial and disadvantageous impacts (8,C11). The protective effect of immune imprinting has been observed in mice sequentially immunized with antigenic drift variants of A(H1N1) viruses, A/Puerto Rico/8/1934 (PR8) and its antigenic variant A/Puerto Rico/8/1934-S12a (S12a), which resulted in higher-affinity antibodies to the primed PR8 HA protein. However, these mice still developed antibodies that reacted to S12a, albeit at a lower HI titer (12). Despite developing a biased antibody response toward PR8, passive transfer Loratadine of PR8-S12a-immune sera protected naive mice from S12a challenge. On the other hand, epidemiological and modeling studies suggest that immune imprinting provides limited protection against antigenically more distinct variants than the imprinted strain (13, 14) due to structural similarity and conserved protective epitopes unique to either group 1 HA or group 2 HA proteins. The immune imprinting patterns of anti-NA antibodies are relatively less studied due in part to the limited knowledge on the NA antigenic changes over time. Seasonal influenza vaccines have focused on generating neutralizing anti-HA antibodies against HA drift variants since the initial licensure in 1945. An observational study reported the age-dependent immune imprinting of anti-NA antibodies using historical N1 and N2 strains that were distantly related in antigenicity (15). It is unknown if age-dependent immune imprinting can be similarly observed using well-defined drifted NA proteins as the virus continues Rabbit polyclonal to PCSK5 to evolve over time. As HA and NA drift variants evolve discordantly (16,C18), the age-dependent anti-HA and anti-NA antibody responses have not been systematically compared in parallel. Here, we characterized the NA antigenicity of seasonal A(H1N1) viruses from 1977 to 1991 to complete the NA antigenic profile of A(H1N1) and A(H1N1)pdm09 viruses circulating in humans. By comparing imprinting patterns of anti-HA and anti-NA antibody responses, a broader cross-reactivity of anti-NA antibody responses than anti-HA antibody responses was observed. RESULTS Antigenic changes in the NA of A(H1N1) seasonal influenza virus, 1977 to 1991. To complete N1 NA antigenic mapping since its reemergence in 1977, we evaluated the NA antigenic changes among A(H1N1) vaccine strains recommended by World Health Organization (WHO) from 1977.