#17,850
Eight years ago, in Science: Protection Against Novel Flu Subtypes Via Childhood HA Imprinting, we looked at research which suggested the influenza HA Group type (1 or 2) you are first exposed to makes a significant, and lasting, impression on your immune system.It is thought this may complicate the creation of `Universal Flu Vaccines', and may well determine how well individuals will fare during the next influenza pandemic; depending upon the pandemic strain, and the flu virus they were first exposed to early in life.
The theory is that if your first influenza exposure was to H1N1 or H2N2 (Group 1), you may carry some limited degree of immunity to H5 viruses (H5N1, H5N6, etc.), while if your first exposure was to H3N2 (Group 2), you may carry some degree of protection against H7 viruses instead (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression).
- Those born prior to the mid-1960s were almost certainly first exposed to Group 1 flu viruses (H1N1 or H2N2)
- Those born after 1968 and before 1977 would have been exposed to Group 2 (H3N2)
- After 1977, both Group 1 and 2 viruses co-circulated, meaning the first exposure could have been to either one.
In China, Indonesia, Cambodia, and Egypt - where most of the H5N1 human infections have been reported - young children were far more likely to be infected than older adults. Conversely, when H7N9 emerged in China (2013-2018), older adults were the primary victims (see H7N9: The Riddle Of The Ages).
In 2010's EID Journal: Original Antigenic Sin And Pandemic H1N1 we saw a letter suggesting OAS as an explanation for the age shift to a younger demographic with novel H1N1, along with a separate commentary (see The Wages of Original Antigenic Sin).
It's complicated, and unfortunately, not entirely consistent.
In January of 2018, in mBio: Pandemic Paradox - Early Life H2N2 Infection Enhanced Mortality From H1N1pdm09, we saw a study finding those born during the 1957 H2N2 pandemic saw the highest mortality in 2009 (see mbio chart below).
H1N1 and H2N2 are both group 1 HA types, and some cross protection might be expected. Also, the mortality rate dropped for those born after 1957 - when H2N2 was still circulating - and didn't spike for those born during the 1968 pandemic when H3N2 (a group 2 HA type) was the only influenza A game in town.
In short, ferrets first exposed group I viruses were far better protected against H5N1 challenge than those first exposed to group 2 influenza viruses.
This is a lengthy, and at times highly technical, research article. I've only posted the introduction, and a few excerpts, so those wanting a deeper dive will want to follow the link to read it in its entirety.
Ivette A. Nuñez1,2 Hyesun Jang1 Ying Huang1 Alyson Kelvin3 Ted M. Ross1,2*1Front. Vet. Sci., 19 December 2023
Sec. Veterinary Infectious Diseases
Volume 10 - 2023 | https://doi.org/10.3389/fvets.2023.1286758
Zoonotic transmission of H5N1 highly pathogenic avian influenza virus (HPAIV) into the human population is an increasing global threat. The recent 2022 HPAIV outbreak significantly highlighted this possibility, increasing concern in the general population. The clinical outcomes of H5N1 influenza virus exposure can be determined by an individual’s primary influenza virus infection (imprinting) or vaccination status.Immunological imprinting with Group 1 - (H1N1, H2N2, and H2N3) increases survival rates following H5N1 viral infection compared to Group 2 - (H3N2) imprinted individuals. Vaccination against H5N1 influenza viruses can offer protection to at-risk populations; however, stockpiled inactivated H5N1 influenza vaccines are not readily available to the public.We hypothesize that the immunological response to vaccination and subsequent clinical outcome following H5N1 influenza virus infection is correlated with the immunological imprinting status of an individual.To test this hypothesis, our lab established a ferret pre-immune model of disease. Naïve ferrets were intranasally inoculated with seasonal influenza viruses and allowed to recover for 84 days prior to H5N1 virus infection.Ferrets imprinted following H1N1 and H2N3 virus infections were completely protected against lethal H5N1 influenza virus challenge (100% survival), with few to no clinical symptoms. In comparison, H3N2 influenza virus-imprinted ferrets had severe clinical symptoms, delayed disease progression, and a sublethal phenotype (40% mortality).Consecutive infections with H1N1 influenza viruses followed by an H3N2 influenza virus infection did not abrogate the immune protection induced by the original H1N1 influenza virus infection. In addition, ferrets consecutively infected with H1N1 and H2N3 viruses had no clinical symptoms or weight loss.H3N2 pre-immune ferrets were vaccinated with a broadly reactive H5 HA-based or H1 NA-based vaccine (Hu-CO 2). These ferrets were protected against H5N1 influenza virus challenge, whereas ferrets vaccinated with the H1N1 wild-type CA/09 rHA vaccine had similar phenotypes as non-vaccinated H3N2-imprinted ferrets with 40% survival. Overall, Group 2 imprinted ferrets, which were vaccinated with heterologous Group 1 HA vaccines, had redirected immune responses to Group 1 influenza viral antigens and rescued a sublethal phenotype to complete protection.
The current H5N1 viral outbreak continues to devastate animal populations including poultry, wild birds, and wild mammals. The individuals responsible for maintaining poultry populations for food and survival are at imminent risk of contracting disease. In addition, the increased incident rate of H5N1 spillover into the human population increases the probability of viral mutation and spread, as has been seen in reports in Ecuador, Cambodia, and Chile (53–55).
Vaccine design and implementation should be a top priority for pandemic preparedness, and the development of an immunogenic universal H5 vaccine will have to consider the pre-immune status of the individuals in question. The specific aims of universal influenza vaccine coverage include the following: 1. all influenza A and B viruses independent of the NA subtype; 2. historical and future influenza strains; 3. pandemic influenza strains; and 4. protection from zoonotic spillover (56, 57).
These goals can be achieved by implementing a chimeric HA vaccine that targets conserved epitopes shared throughout H5 viral clades, addressing the problematic accelerated evolution of the H5 virus HA protein.
(Continue . . . )In this study, we demonstrated the protective effects of group 1 influenza pre-immunity against H5N1 viral challenge, and the variable effects of group 2 H3N2 pre-immunity that can be rescued with a one-dose vaccination using a highly immunogenic broadly reactive HA antigen Human COBRA 2 formulated with adjuvant. The efficacy of the H5 Human COBRA 2 vaccine and its predecessors will continue to be investigated in animal models of disease (46), and further studies will be conducted to access immunogenicity in a pre-immunological background against new variant H5 viral strains.
But this research does reinforce the idea that the first influenza virus our immune system encounters can shape our immune response for the rest of our lives.
And given our precarious relationships with emerging zoonotic influenza viruses, every bit of insight helps.
