Negative Effect of Age, but Not of Latent Cytomegalovirus Infection on the Antibody Response to a Novel Influenza Vaccine Strain in Healthy Adults

Abstract

Older adults are more vulnerable to influenza virus infection and at higher risk for severe complications and influenza-related death compared to younger adults. Unfortunately, influenza vaccine responses tend to be impaired in older adults due to aging of the immune system (immunosenescence). Latent infection with cytomegalovirus (CMV) is assumed to enhance age-associated deleterious changes of the immune system. Although lower responses to influenza vaccination were reported in CMV-seropositive compared to CMV-seronegative adults and elderly, beneficial effects of CMV infection were observed as well. The lack of consensus in literature on the effect of latent CMV infection on influenza vaccination may be due to the presence of pre-existing immunity to influenza in these studies influencing the subsequent influenza vaccine response. We had the unique opportunity to evaluate the effect of age and latent CMV infection on the antibody response to the novel influenza H1N1pdm vaccine strain during the pandemic of 2009, thereby reducing the effect of pre-existing immunity on the vaccine-induced antibody response. This analysis was performed in a large study population (n = 263) in adults (18–52 years old). As a control, memory responses to the seasonal vaccination, including the same H1N1pdm and an H3N2 strain, were investigated in the subsequent season 2010–2011. With higher age, we found decreased antibody responses to the pandemic vaccination even within this age range, indicating signs of immunosenescence to this novel antigen in the study population. Using a generalized estimation equation regression model, adjusted for age, sex, and previous influenza vaccinations, we observed that CMV infection in contrast did not influence the influenza virus-specific antibody titer after H1N1pdm vaccination. Yet, we found higher residual protection rates (antibody level ≥40 hemagglutinin units (HAU)) in CMV-seropositive individuals than in CMV-seronegative individuals 6 months and 1 year after pandemic vaccination. In the subsequent season, no effect of age or CMV infection on seasonal influenza vaccine response was observed. In conclusion, we observed no evidence for CMV-induced impairment of antibody responses to a novel influenza strain vaccine in adults. If anything, our data suggest that there might be a beneficial effect of latent CMV infection on the protection rate after novel influenza vaccination.

Reduced Ebola vaccine responses in CMV+ young adults is associated with expansion of CD57+KLRG1+ T cells

“…CMV-specific CD4 + T cells are thought to play an important role in containing CMV infection, and in mouse models, CD4 + T cells were abundant in infected peripheral tissues (Reuter et al, 2005;Verma et al, 2015). A reduction in the CD4:CD8 ratio in healthy young CMV + adults, which has also been reported in other studies (Turner et al, 2014), could be caused by a reduction in circulating CD4 + T cells as they are recruited to peripheral sites of infection. As infected individuals age, multiple reactivation events over many decades cause a gradual expansion of CMV-specific CD8 + T cells, which then become the prominent factor driving the CD4:CD8 ratio down (Hadrup et al, 2006).…”

“…Although a range of studies have shown contradictory findings on the impact of CMV on immune responses, with some demonstrating a negative effect (Trzonkowski et al, 2003;Derhovanessian et al, 2013;Turner et al, 2014;Frasca et al, 2015;Wagner et al, 2018), some a positive effect (Miles et al, 2008;Holder et al, 2010;Wald et al, 2013;Furman et al, 2015), and others no effect (den Elzen et al, 2011;O'Connor et al, 2014), it is likely that a combination of factors contributes to these differing results. First, the impact of CMV on heterologous immune responses may differ between primary and memory responses.…”

‘From immunosenescence to immune modulation’: a re-appraisal of the role of cytomegalovirus as major regulator of human immune function

“…The efficacy of response to vaccine challenge has been used as a surrogate of immune competence in many studies and an impairment of influenza-specific antibody titre has been reported (62)(63)(64). However, other studies have failed to show any association between CMV carriage and either the breadth or titre of neutralising antibodies (65)(66)(67). As such, the importance of CMV infection as a determinant of immune competence remains uncertain.…”

Cytomegalovirus infection and progressive differentiation of effector-memory T cells

“…Whether progressive EM T-cell differentiation is a non-functional response against the persistent presence of CMV antigens or a functional adaptation of the CMV-reactive T cells to keep control over CMV infection is unknown, but it may affect cellular function and senescence. In humans, latent CMV infection in older individuals resulted in lower protection rates after vaccination with an influenza vaccine 30 – 32 ; however, neutral effects of CMV infection were also observed 33 – 36 . Possibly related to some of these studies is the finding that high-dose but not low-dose CMV infection impairs the development of a heterologous anti-viral T-cell response 24 , 37 , 38 .…”