Meeting NewsPerspective

Small study finds no clear imprinting effect on flu vaccination based on ‘first flu’

In a small study, researchers did not see a strong imprinting effect on influenza vaccination based on when participants were born, according to data presented at the National Foundation for Infectious Diseases’ Annual Conference on Vaccinology Research.

Amy Sherman, MD, an infectious disease fellow at Emory University, and colleagues studied 20 total participants in two cohorts: those born between 1948 and 1957, and those born between 1968 and 1977.

“Based on epidemiological data, H1N1 was the primary strain circulating before 1957, and H3N2 was the primary strain circulating between 1968 and 1977,” Sherman explained to Infectious Disease News. “[According to] the theory of imprinting and the doctrine of original antigenic sin, individuals produce the most robust immune response to the first influenza A virus they encountered as a child, even when they encounter novel influenza viruses later in life. Based on this theory, the birth cohorts were defined to select for individuals who were born in these specific years, to see if there was an imprinting effect based on the ‘first flu’ that they encountered as a child.”

Imprinting results

According to the study, Sherman and colleagues hypothesized that participants born between 1948 and 1957 would produce more robust hemagglutination-inhibition antibody (HAI) and cellular responses to the H1N1 component of the seasonal vaccine compared with the other three vaccine components, whereas participants born from 1968 to 1977 would produce more robust HAI antibody and cellular responses to the H3N2 component.

To test this hypothesis, they conducted a prospective pilot study, dividing the 20 participants evenly into the two cohorts. Among each cohort, participants were separated again by those who had received the influenza vaccine in 2 of the past 5 years and those who had received it at least 3 of the past 5 years, so that Sherman and colleagues also could study the effect of repeated vaccination.

According to the study, participants will complete six visits on days 1, 3, 8, 15, 29, and 180, with blood drawn at baseline, followed by vaccination with the 2018-2019 quadrivalent influenza vaccine. Sherman and colleagues assessed the levels of antigen-specific antibody secreting cells (ASCs) against each strain at day 8 and determined the proportion of study participants who achieved seroprotection or seroconversion against the four vaccine strains, as measured by HAI antibody response.

According to Sherman, there was no preferential response to H1N1 in the H1N1 birth cohort or to H3N2 in the H3N2 cohort. Explaining some limitations, she said this could be because they only looked at ASCs and HAI titers, because it was a small study with only 20 individuals, or because the cohorts were based on epidemiological data based on primary circulating influenza strains at their birth year.

“We don’t have a way to actually prove which strain individuals were first exposed to,” she said.

Repeated vaccination

According to Sherman, data showed that participants who received minimal vaccinations in the past 5 years had a higher magnitude response of ASCs and a higher HAI fold change, representing seroconversion “and thus protection against flu.”

However, she noted that a HAI fold change greater than 40 also is indicative of protection, and that among the repeated vaccination group, individuals started at a high HAI titer at baseline, well over the level of 40, indicating they may have a certain amount of pre-existing protection to influenza from prior vaccination, Sherman said.

“So it’s not strong enough data to recommend against seasonal annual influenza [vaccination] at this point,” she told Infectious Disease News.

According to Sherman, learning how imprinting and repeated vaccination impact protection against influenza may help the development of an effective universal influenza vaccine.

“We know that influenza still contributes to morbidity and mortality. Last year was especially bad — not just in mortality but in the number of cases and hospitalizations that represent a significant cost and burden to society. And although we have seasonal flu vaccines, we know that there are several limitations to these which limit the overall efficacy of our vaccines,” Sherman said during a news conference.

“Many of these [limitations] are being discussed at this conference but the one that we wanted to focus on is the variability in host response to the flu vaccine. The reason this is so important is because there is an urgent need to develop a universal flu vaccine that is at least 75% effective, provides coverage for multiple strains, and [is] durable.” – by Caitlyn Stulpin

Reference:

Sherman A, et al. Abstract 1-4. Presented at: NFID Annual Conference on Vaccinology Research; April. 3-5, 2019; Baltimore.

Disclosure: Sherman reports no relevant financial disclosures.

In a small study, researchers did not see a strong imprinting effect on influenza vaccination based on when participants were born, according to data presented at the National Foundation for Infectious Diseases’ Annual Conference on Vaccinology Research.

Amy Sherman, MD, an infectious disease fellow at Emory University, and colleagues studied 20 total participants in two cohorts: those born between 1948 and 1957, and those born between 1968 and 1977.

“Based on epidemiological data, H1N1 was the primary strain circulating before 1957, and H3N2 was the primary strain circulating between 1968 and 1977,” Sherman explained to Infectious Disease News. “[According to] the theory of imprinting and the doctrine of original antigenic sin, individuals produce the most robust immune response to the first influenza A virus they encountered as a child, even when they encounter novel influenza viruses later in life. Based on this theory, the birth cohorts were defined to select for individuals who were born in these specific years, to see if there was an imprinting effect based on the ‘first flu’ that they encountered as a child.”

Imprinting results

According to the study, Sherman and colleagues hypothesized that participants born between 1948 and 1957 would produce more robust hemagglutination-inhibition antibody (HAI) and cellular responses to the H1N1 component of the seasonal vaccine compared with the other three vaccine components, whereas participants born from 1968 to 1977 would produce more robust HAI antibody and cellular responses to the H3N2 component.

To test this hypothesis, they conducted a prospective pilot study, dividing the 20 participants evenly into the two cohorts. Among each cohort, participants were separated again by those who had received the influenza vaccine in 2 of the past 5 years and those who had received it at least 3 of the past 5 years, so that Sherman and colleagues also could study the effect of repeated vaccination.

According to the study, participants will complete six visits on days 1, 3, 8, 15, 29, and 180, with blood drawn at baseline, followed by vaccination with the 2018-2019 quadrivalent influenza vaccine. Sherman and colleagues assessed the levels of antigen-specific antibody secreting cells (ASCs) against each strain at day 8 and determined the proportion of study participants who achieved seroprotection or seroconversion against the four vaccine strains, as measured by HAI antibody response.

According to Sherman, there was no preferential response to H1N1 in the H1N1 birth cohort or to H3N2 in the H3N2 cohort. Explaining some limitations, she said this could be because they only looked at ASCs and HAI titers, because it was a small study with only 20 individuals, or because the cohorts were based on epidemiological data based on primary circulating influenza strains at their birth year.

“We don’t have a way to actually prove which strain individuals were first exposed to,” she said.

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Repeated vaccination

According to Sherman, data showed that participants who received minimal vaccinations in the past 5 years had a higher magnitude response of ASCs and a higher HAI fold change, representing seroconversion “and thus protection against flu.”

However, she noted that a HAI fold change greater than 40 also is indicative of protection, and that among the repeated vaccination group, individuals started at a high HAI titer at baseline, well over the level of 40, indicating they may have a certain amount of pre-existing protection to influenza from prior vaccination, Sherman said.

“So it’s not strong enough data to recommend against seasonal annual influenza [vaccination] at this point,” she told Infectious Disease News.

According to Sherman, learning how imprinting and repeated vaccination impact protection against influenza may help the development of an effective universal influenza vaccine.

“We know that influenza still contributes to morbidity and mortality. Last year was especially bad — not just in mortality but in the number of cases and hospitalizations that represent a significant cost and burden to society. And although we have seasonal flu vaccines, we know that there are several limitations to these which limit the overall efficacy of our vaccines,” Sherman said during a news conference.

“Many of these [limitations] are being discussed at this conference but the one that we wanted to focus on is the variability in host response to the flu vaccine. The reason this is so important is because there is an urgent need to develop a universal flu vaccine that is at least 75% effective, provides coverage for multiple strains, and [is] durable.” – by Caitlyn Stulpin

Reference:

Sherman A, et al. Abstract 1-4. Presented at: NFID Annual Conference on Vaccinology Research; April. 3-5, 2019; Baltimore.

Disclosure: Sherman reports no relevant financial disclosures.

    Perspective
    William Schaffner

    William Schaffner

    I think the overriding perspective I have is the rather rueful acknowledgment that we still have an imperfect understanding between this terribly important virus and our immune system. We still have a murky understanding about what it is and what our immune response is to the virus in all its forms. This reminds me of that adage: “We call it research because it’s not a straight line, otherwise we’d call it search.” So, we must keep going back and try to dissect the immune response that we have to influenza and understand it substantially better. If we did that, we could very quickly create what we all desire — a much improved, more effective influenza vaccine. Of course, we know there are a number of investigators pursing that at the given time. But while they do, in the meantime, manufacturers and investigators must continue trying to improve the influenza vaccine in baby steps. They are making some small, noteworthy advances, but we are still looking for major advances.

    • William Schaffner, MD
    • Infectious Disease News Editorial Board member
      Professor of preventive medicine,
      Vanderbilt University School of Medicine
      Medical director,
      National Foundation for Infectious Diseases

    Disclosures: Schaffner serves as an advisor or consultant for Dynavax, Merck, Novavax, Pfizer, Roche, Seqirus, Shionogi and SutroVax.

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