Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely characterized. We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain (RBD), ACE2 displacement and viral neutralization activities one month following the first and second COVID-19 vaccine doses, and again 3 months following the second dose, in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525–935) cells/mm3, though nadir CD4+ T-cell counts ranged as low as <10 cells/mm3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was associated with lower anti-RBD antibody concentrations and ACE2 displacement activity after one vaccine dose. Following two doses however, HIV was not significantly associated with the magnitude of any humoral response after multivariable adjustment. Rather, older age, a higher burden of chronic health conditions, and dual ChAdOx1 vaccination were associated with lower responses after two vaccine doses. No significant correlation was observed between recent or nadir CD4+ T-cell counts and responses to two vaccine doses in PLWH. These results indicate that PLWH with well-controlled viral loads and CD4+ T-cell counts in a healthy range generally mount strong initial humoral responses to dual COVID-19 vaccination. Factors including age, co-morbidities, vaccine brand, response durability and the rise of new SARS-CoV-2 variants will influence when PLWH will benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment or who have low CD4+ T-cell counts are needed, as are longer-term assessments of response durability.

Background The magnitude and durability of immune responses to COVID-19 mRNA vaccines remain incompletely characterized in the elderly. Methods Anti-spike RBD antibodies, ACE2 competition and virus neutralizing activities were assessed in plasma from 151 healthcare workers and older adults (range 24-98 years of age) one month following the first vaccine dose, and one and three months following the second dose. Results Older adults exhibited significantly weaker responses than younger healthcare workers for all humoral measures evaluated and at all time points tested, except for ACE2 competition activity after one vaccine dose. Moreover, older age remained independently associated with weaker responses even after correction for sociodemographic factors, chronic health condition burden, and vaccine-related variables. By three months after the second dose, all humoral responses had declined significantly in all participants, and remained significantly lower among older adults, who also displayed reduced binding antibodies and ACE2 competition activity towards the Delta variant. Conclusions Humoral responses to COVID-19 mRNA vaccines are significantly weaker in older adults, and antibody-mediated activities in plasma decline universally over time. Older adults may thus remain at elevated risk of infection despite vaccination.

Background Third COVID-19 vaccine doses are broadly recommended, but immunogenicity data remain limited, particularly in older adults. Methods We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement, and virus neutralization against ancestral and Omicron (BA.1) strains from pre-vaccine up to one month following the third dose, in 151 adults aged 24-98 years who received COVID-19 mRNA vaccines. Results Following two vaccine doses, humoral immunity was weaker, less functional and less durable in older adults, where a higher number of chronic health conditions was a key correlate of weaker responses and poorer durability. One month after the third dose, antibody concentrations and function exceeded post-second-dose levels, and responses in older adults were comparable in magnitude to those in younger adults at this time. Humoral responses against Omicron were universally weaker than against the ancestral strain after both the second and third doses. Nevertheless, after three doses, anti-Omicron responses in older adults reached equivalence to those in younger adults. One month after three vaccine doses, the number of chronic health conditions, but not age, was the strongest consistent correlate of weaker humoral responses. Conclusion Results underscore the immune benefits of third COVID-19 vaccine doses, particularly in older adults.

Background. Our understanding of COVID-19 vaccine immune responses in people living with HIV (PLWH) remains incomplete. Methods. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and ACE2 displacement activities after one and two COVID-19 vaccine doses in 100 adult PLWH and 152 controls. Results. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm3. Median nadir CD4+ T-cell counts were 280 (IQR 120-490) cells/mm3, and ranged as low as 9 cells/mm3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was associated with 0.2 log10 lower anti-RBD antibody concentrations (p=0.03) and ~7% lower ACE2 displacement activity (p=0.037) after one vaccine dose. Following two vaccine doses however, the association between HIV and weaker responses no longer remained. Rather, older age, a higher burden of chronic health conditions, and having received two ChAdOx1 doses (as opposed to a heterologous or dual mRNA vaccine regimen) were the most significant correlates of weaker humoral responses. No significant association was observed between the most recent or nadir CD4+ T-cell counts and responses to COVID-19 vaccination in PLWH following two vaccine doses. Conclusions. These results suggest that PLWH whose viral loads are well-controlled on antiretroviral therapy and whose CD4+ T-cell counts are in a healthy range will generally not require a third COVID-19 vaccine dose as part of their initial immunization series, though other factors such as older age, co-morbidities, type of initial vaccine regimen and durability of vaccine responses will influence when this group may benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment and/or who have low CD4+ T-cell counts are needed.

Background mRNA vaccines reduce COVID-19 incidence and severity, but the durability of vaccine-induced immune responses, particularly among the elderly, remains incompletely characterized. Methods Anti-spike RBD antibody titers, ACE2 competition and virus neutralizing activities were longitudinally assessed in 151 healthcare workers and older adults (overall aged 24-98 years) up to three months after vaccination. Results Older adults exhibited lower antibody responses after one and two vaccine doses for all measures. In multivariable analyses correcting for sociodemographic, chronic health and vaccine-related variables, age remained independently associated with all response outcomes. The number of chronic health conditions was additionally associated with lower binding antibody responses after two doses, and male sex with lower ACE2 competition activity after one dose. Responses waned universally at three months after the second dose, but binding antibodies, ACE2 competition and neutralizing activities remained significantly lower with age. Older adults also displayed reduced ability to block ACE2 binding by the Delta variant. Conclusions The humoral immune response to COVID-19 mRNA vaccines is significantly weaker with age, and universally wanes over time. This will likely reduce antibody-mediated protection against SARS-CoV-2 and the Delta variant as the pandemic progresses. Older adults may benefit from additional immunizations as a priority.

Background. Two-dose mRNA vaccines reduce COVID-19 related hospitalization and mortality, but immune protection declines over time. As such, third vaccine doses are now recommended, particularly for older adults. We examined immune response durability up to 6 months after two vaccine doses, and immunogenicity after a third vaccine dose, in 151 adults ranging in age from 24 to 98 years. Methods. Specimens were collected from 81 healthcare workers (median age 41 years), 56 older adults (median 78 years) and 14 COVID-19 convalescent individuals (median 48 years), at one, three and six months following the second dose, and from 15 HCW, 28 older adults and 3 convalescent individuals at one month following a third dose. Binding antibodies to the SARS-CoV-2 spike receptor binding domain were quantified using a commercial immunoassay. Virus neutralizing activity was assessed using a live SARS-CoV-2 infection assay. Results. Compared to healthcare workers, older adults displayed ~0.3 log10 lower peak binding antibodies one month after the second dose (p<0.0001) and modestly faster rates of antibody decline thereafter (p=0.0067). A higher burden of chronic health conditions was independently associated with faster rates of antibody decline after correction for age, sociodemographic factors, and vaccine-related variables. Peak neutralizing activity was 4-fold lower in older adults one month after the second dose (p<0.0001) and became undetectable in the majority of individuals by six months. One month after a third dose, binding antibodies and neutralizing activities surpassed peak values achieved after two doses in both healthcare workers and older adults, and differences between these groups were no longer statistically significant. Compared to both naive groups, convalescent individuals displayed slower rates of binding antibody decline (p<0.006) and maintained higher neutralizing activity six months after the second dose. Conclusions. Immune responses to two-dose COVID-19 mRNA vaccines are overall weaker in older adults, and also decline more quickly over time, compared to younger adults. A third COVID-19 mRNA vaccine dose enhanced binding and neutralizing antibodies to levels higher than those observed after two vaccine doses, but the rate of decline of these responses should be monitored, particularly in older adults with a higher burden of chronic health conditions.

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