3. Impact of CMV Infection on Response to Pathogens and Vaccines
Although difficult to assess due the heterogeneity of underlying comorbidities, age-induced impairment of both quantitative and qualitative immune system responses leads to a decreased response to vaccination 
. With advancing age, total antibody titers decrease significantly 
, and the quality of these antibodies is also reduced 
. Regarding the T-cell compartment, the number and immune repertoire of naïve T-cells available to respond to vaccine stimulation decreases with age as a result of thymic involution 
. Moreover, accumulation of terminally differentiated cells, with a senescent phenotype and altered effector function is also a hallmark of aging.
Cytomegalovirus is partly responsible for the progressive inflation of the T-cell memory compartment, due to repeated antigen stimulation, however, its direct effect on response to pathogens and vaccines remains debated. Nevertheless, there is mounting evidence that CMV-seropositivity is associated with a reduced response to both invasion with a novel pathogen and to vaccination.
Influence of CMV in response to pathogens has been studied in mice, where CMV-specific CD8 T-cell expansion has been associated with a decreased T-cell repertoire available for response against other pathogens and decreased CD8 T-cell response upon influenza or West Nile virus superinfection 
. However, this association is not consistently reported 
. Again in a mouse model, immune activation due to recent infection with mCMV and other pathogens (murine γ-herpesvirus 68, influenza and helminth) was also associated with an decreased antibody response to yellow fever vaccine YF-17D 
. In human studies, CMV-induced memory inflation was associated with a decreased memory response to EBV 
and to influenza 
in older people. Although not extensively studied yet, its role in the clinical course and severity of coronavirus disease 2019 (COVID-19) has also been proposed, due to the probable role of immunosenescence in the increased vulnerability of older patients 
The influence of CMV on the immune response to vaccination remains a matter of debate. In particular, many studies aimed to assess the influence of CMV in the immune response to influenza vaccination in the elderly, as the protection in this population remains unsatisfactory. In 2003, Trzonkowski et al. reported in 154 young and older individuals a negative correlation between responses to influenza trivalent inactivated vaccination (TIV) and anti-CMV IgGs, higher percentages of CD57+
lymphocytes, and higher circulating levels of TNF-α and IL-6 
. Derhovanessian et al. reported a negative association between CMV seropositivity and antibody titers after influenza immunization in an elderly population, but not in participants below 60 years of age 
. In contrast, a study conducted by Wald et al. reported increased antibody titers only in CMV-seronegative vs. -seropositive participants below 60 years of age, whereas no difference could be observed in an older group 
. A recent meta-analysis on the response rate to influenza vaccination revealed a trend for a decreased response in CMV-seropositive compared to CMV-seronegative participants 
. Altogether, an impact of CMV on response to influenza vaccine can be assumed, although not unequivocally due to inconsistent reports. Larger and more systematic studies are needed to shed light on the influence of CMV latent infection on the influenza vaccine response.
Regarding other vaccines, a study evaluated the response to Ebola vaccine candidates (ChAd3-EBO-Z and MVA-EBO-Z) in healthy young adults in both the UK and Senegal 
. CMV seropositivity was negatively associated with vaccine response in both UK and Senegalese cohorts, and correlated with an expansion of phenotypically senescent CD4 and CD8 T cells expressing CD57. Concerning vaccines against SARS-CoV-2, few PLWH have been included in the phase III vaccine trials, and constituted only 0.5% and 0.6% of participants in the Pfizer and Moderna trials, respectively 
. Dedicated studies are thus urgently needed to evaluate the immunity after immunization against SARS-CoV-2 in PLWH.
Few studies have also been conducted in patients with comorbidities. In a recent study evaluating the response to vaccines in patients with chronic kidney disease, CMV seropositivity emerged as the stronger predictor of poor responsiveness to 23-valent pneumococcal polysaccharide PPV23 vaccination, rather than chronic kidney disease itself 
. Conversely, in the same study, CMV seropositivity did not impact the response to trivalent inactivated influenza vaccine. A study also evaluated the response to influenza vaccination in patients with type 2 diabetes mellitus (T2DM), compared to healthy age-matched controls 
. Whereas T2DM was not associated with a difference in response, CMV-seropositive participants responded surprisingly significantly better to vaccine than CMV-seronegative participants, in both healthy and diabetic participants.
Finally, in a proof-of-concept clinical trial, 36 CMV-seropositive patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis received either 6 months of valacyclovir or placebo 
. Cytomegalovirus subclinical reactivation in these participants was associated with an impaired response to PCV13 pneumococcal vaccination. In comparison, antiviral suppression with valacyclovir could prevent reactivation events, decreased the abundance of CD4+
T-cells and increased vaccine response.
In infants with antenatal or postnatal CMV infection, studies have also evaluated the effect of CMV on response to vaccines, especially in poor-resource settings where the majority of children are infected before their first year of life 
. CMV-induced alterations of immune response to measles and to a lesser extent to polio vaccines have been reported, whereas no difference in the response to Hib or tetanus vaccines were reported 
. Interestingly, a study evaluating the immune response to oral polio vaccine in Zambian infants suggested a synergistic negative effect of HIV and CMV coinfection on the antibody response