Historical H1N1 Influenza Virus Imprinting Increases Vaccine Protection by Influencing the Activity and Sustained Production of Antibodies Elicited at Vaccination in Ferrets

Abstract

Influenza virus imprinting is now understood to significantly influence the immune responses and clinical outcome of influenza virus infections that occur later in life. Due to the yearly cycling of influenza viruses, humans are imprinted with the circulating virus of their birth year and subsequently build a complex influenza virus immune history. Despite this knowledge, little is known about how the imprinting strain influences vaccine responses. To investigate the immune responses of the imprinted host to split-virion vaccination, we imprinted ferrets with a sublethal dose of the historical seasonal H1N1 strain A/USSR/90/1977. After a +60-day recovery period to build immune memory, ferrets were immunized and then challenged on Day 123. Antibody specificity and recall were investigated throughout the time course. At challenge, the imprinted vaccinated ferrets did not experience significant disease, while naïve-vaccinated ferrets had significant weight loss. Haemagglutination inhibition assays showed that imprinted ferrets had a more robust antibody response post vaccination and increased virus neutralization activity. Imprinted-vaccinated animals had increased virus-specific IgG antibodies compared to the other experimental groups, suggesting B-cell maturity and plasticity at vaccination. These results should be considered when designing the next generation of influenza vaccines.

Predominance of a Drifted Influenza A (H3N2) Clade and Its Association with Age-Specific Influenza Vaccine Effectiveness Variations, Influenza Season 2018–2019

“…Furthermore, it has been proposed that influenza viruses that circulate during a person's childhood can confer lasting protection against new influenza viruses that belong to a similar phylogenetic group [24]. In this regard, ferrets that were vaccinated with a split-virion influenza vaccine following influenza A (H1N1) A/USSR/90/1977 infection earlier in their life showed less illness after infection with influenza A (H1N1)pdm09 A/California/07/2009 as compared with vaccinated ferrets who were not previously infected with influenza A (H1N1) A/USSR/90/1977 [25]. Moreover, it was recently shown that recurring exposures to influenza A (H3) in humans was associated with higher antibody titers, enhanced antibody affinity, as well as enhanced antibody avidity following influenza vaccination, as compared with individuals not previously exposed [26].…”

Immune Imprinting in the Influenza Ferret Model

“…Emphasis was placed on the concept that testing vaccine candidates in naïve ferrets do not reflect the performance of the vaccines in the human population. In an A(H1N1) primed model, greater protection after vaccination was observed [18].…”

“…The first influenza strain that infects a human or animal is the imprinting virus for that individual [5,18]. This initial strain biases the immune memory response to subsequent infections in a phenomenon described as "original antigenic sin".…”

“…Although imprinting was initially characterized by serological results, the basis of this phenomenon is cellular, with the initial infection driving the production of long-lasting virus specific B-and T-memory cells that bias the immune response to subsequence viruses [25]. After this initial infection, pre-existing immunity is the culmination of the first and all following exposures and can also be referred to as an individual's entire influenza history [18]. A pre-immune individual is one with any immune memory to influenza.…”

Pre-existing immunity provides a barrier to airborne transmission of influenza viruses

“…As demonstrated in Figure 1, ferrets are naturally susceptible to human H1N1pdm09 and H3N2 influenza virus infections. To develop a model to mimic the yearly seasonality of influenza infections, we waited between 60 and 84 days between infections to allow for the primary immune response to wane, as shown by others (19)(20)(21)(22), and result in two robust infections. Six ferrets were infected with H3N2 virus and then three of those animals were experimentally infected at 60 days post-infection with H1N1pdm09 virus (herein referred to as 'H3-H1 INF') ( Fig 2A).…”