Antibody response durability following three-dose COVID-19 vaccination in people with HIV receiving suppressive ART

BackgroundLimited data exist regarding longer-term antibody responses following three-dose COVID-19 vaccination, and the impact of a first SARS-CoV-2 infection during this time, in people living with HIV (PLWH) receiving suppressive antiretroviral therapy (ART). We quantified wild-type-(WT), Omicron BA.1- and Omicron BA.5-specific responses up to six months post-third dose in 64 PLWH and 117 controls who remained COVID-19-naive or experienced their first SARS-CoV-2 infection during this time. DesignLongitudinal observational cohort. MethodsWe quantified WT- and Omicron-specific Anti-Spike receptor-binding domain IgG concentrations, ACE2 displacement activities and live virus neutralization at one, three and six months post-third vaccine dose. ResultsThird doses boosted all antibody measures above two-dose levels, but BA.1-specific responses remained significantly lower than WT-specific ones, with BA.5-specific responses lower still. Serum IgG concentrations declined at similar rates in COVID-19-naive PLWH and controls post-third dose (median WT- and BA.1-specific half-lives were between 66-74 days for both groups). Antibody function also declined significantly yet comparably between groups: six months post-third dose, BA.1-specific neutralization was undetectable in >80% of COVID-19 naive PLWH and >90% of controls. Breakthrough SARS-CoV-2 infection boosted antibody concentrations and function significantly above vaccine-induced levels in both PLWH and controls, though BA.5-specific neutralization remained significantly poorer than BA.1 even post-breakthrough. ConclusionsFollowing three-dose COVID-19 vaccination, antibody response durability in PLWH receiving ART is comparable to controls. PLWH also mounted strong responses to breakthrough infection. Due to temporal response declines however, COVID-19-naive individuals, regardless of HIV status, would benefit from a fourth dose within 6 months of their third.

Brief Report: Impact of age and SARS-CoV-2 breakthrough infection on humoral immune responses after three doses of COVID-19 mRNA vaccine

BackgroundLonger-term immune response data after three doses of COVID-19 mRNA vaccine remain limited, particularly among older adults and following Omicron breakthrough infection. MethodsWe quantified wild-type- and Omicron-specific serum IgG levels, ACE2 displacement activities and live virus neutralization up to six months post-third dose in 116 adults aged 24-98 years who remained COVID-19-naive or experienced their first SARS-CoV-2 infection during this time. ResultsAmong 78 participants who remained COVID-19-naive throughout follow-up, wild-type- and Omicron BA.1-specific IgG concentrations were comparable between younger and older adults, though BA.1-specific responses were consistently significantly lower than wild-type-specific responses in both groups. Wild-type- and BA.1-specific IgG concentrations declined at similar rates among COVID-19-naive younger and older adults, with median half-lives ranging from 69-78 days. Antiviral antibody function declined substantially over time in COVID-19-naive individuals, particularly older adults: by six months, BA.1-specific neutralization was undetectable in 96% of older adults, versus 56% of younger adults. SARS-CoV-2 infection, experienced by 38 participants, boosted IgG levels and neutralization above those induced by vaccination alone. Nevertheless, BA.1-specific neutralization remained significantly lower than wild-type, with BA.5-specific neutralization lower still. ConclusionsOur findings underscore the immune benefits of third COVID-19 mRNA vaccine doses in adults of all ages, but rapid decline of Omicron-specific neutralization activity in COVID-19-naive individuals, particularly among older adults, demonstrates the need for fourth doses within 3-6 months to maintain systemic responses. Individuals who experienced SARS-CoV-2 breakthrough infection post-third vaccine dose however can likely delay a fourth dose beyond this timeframe.

Serial infection with SARS-CoV-2 Omicron BA.1 and BA.2 following three-dose COVID-19 vaccination

SARS-CoV-2 Omicron infections are common among individuals who are vaccinated or have recovered from prior variant infection, but few reports have documented serial Omicron infections. We characterized SARS-CoV-2 humoral responses in a healthy young person who acquired laboratory-confirmed Omicron BA.1.15 ten weeks after a third dose of BNT162b2, and BA.2 thirteen weeks later. Responses were compared to those of 124 COVID-19 naive vaccinees. One month after the second and third vaccine doses, the participants wild-type and BA.1-specific IgG, ACE2 competition and virus neutralization activities were average for a COVID-19 naive triple-vaccinated individual. BA.1 infection boosted the participants responses to the cohort [≥]95th percentile, but even this strong "hybrid" immunity failed to protect against BA.2. Moreover, reinfection increased BA.1 and BA.2-specific responses only modestly. Results illustrate the risk of Omicron infection in fully vaccinated individuals and highlight the importance of personal and public health measures as vaccine-induced immune responses wane.

People with HIV receiving suppressive antiretroviral therapy show typical antibody durability after dual COVID-19 vaccination, and strong third dose responses

BackgroundLonger-term humoral responses to two-dose COVID-19 vaccines remain incompletely characterized in people living with HIV (PLWH), as do initial responses to a third dose. MethodsWe measured antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement and viral neutralization against wild-type and Omicron strains up to six months following two-dose vaccination, and one month following the third dose, in 99 PLWH receiving suppressive antiretroviral therapy, and 152 controls. ResultsThough humoral responses naturally decline following two-dose vaccination, we found no evidence of lower antibody concentrations nor faster rates of antibody decline in PLWH compared to controls after accounting for sociodemographic, health and vaccine-related factors. We also found no evidence of poorer viral neutralization in PLWH after two doses, nor evidence that a low nadir CD4+ T-cell count compromised responses. Post-third-dose humoral responses substantially exceeded post-second-dose levels, though anti-Omicron responses were consistently weaker than against wild-type. Nevertheless, post-third-dose responses in PLWH were comparable to or higher than controls. An mRNA-1273 third dose was the strongest consistent correlate of higher post-third-dose responses. ConclusionPLWH receiving suppressive antiretroviral therapy mount strong antibody responses after two- and three-dose COVID-19 vaccination. Results underscore the immune benefits of third doses in light of Omicron.

Older Adults Mount Less Durable Humoral Responses to a Two-dose COVID-19 mRNA Vaccine Regimen, but Strong Initial Responses to a Third Dose

BackgroundThird COVID-19 vaccine doses are broadly recommended, but immunogenicity data remain limited, particularly in older adults. MethodsWe 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. ResultsFollowing 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. Third doses boosted antibody binding and function to higher levels than second-doses, and induced responses in older adults that were comparable in magnitude to those in younger adults. Humoral responses against Omicron were universally weaker than against the ancestral strain after both second and third doses; nevertheless, after three doses, anti-Omicron responses in older adults reached equivalence to those in younger adults. After three vaccine doses, the number of chronic health conditions, but not age per se, was the strongest consistent correlate of weaker humoral responses. ConclusionResults underscore the immune benefits of third COVID-19 vaccine doses, particularly in older adults.

Humoral immune responses to COVID-19 vaccination in people living with HIV on suppressive antiretroviral therapy

Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely understood. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, ACE2 displacement and live viral neutralization activities one month following the first and second COVID-19 vaccine doses 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. Nadir CD4+ T-cell counts ranged as low as <10 (median 280; IQR 120-490) cells/mm3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was significantly associated with 0.2 log10 lower anti-RBD antibody concentrations (p=0.03) and [~]11% lower ACE2 displacement activity (p=0.02), but not lower viral neutralization (p=0.1) after one vaccine dose. Following two doses however, HIV was no longer significantly associated with the magnitude of any response measured. Rather, older age, a higher burden of chronic health conditions, and having received two ChAdOx1 doses (versus a heterologous or dual mRNA vaccine regimen) were independently associated with lower responses. After two vaccine doses, no significant correlation was observed between the most recent or nadir CD4+ T-cell counts and vaccine responses in PLWH. These results suggest that PLWH with well-controlled viral loads on antiretroviral therapy and CD4+ T-cell counts 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, vaccine regimen type, 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.

Reduced magnitude and durability of humoral immune responses by COVID-19 mRNA vaccines among older adults

BackgroundmRNA vaccines reduce COVID-19 incidence and severity, but the durability of vaccine-induced immune responses, particularly among the elderly, remains incompletely characterized. MethodsAnti-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. ResultsOlder 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. ConclusionsThe 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.

Weak humoral immune reactivity among residents of long-term care facilities following one dose of the BNT162b2 mRNA COVID-19 vaccine

BackgroundSeveral Canadian provinces are extending the interval between COVID-19 vaccine doses to increase population vaccine coverage more rapidly. However, immunogenicity of these vaccines after one dose is incompletely characterized, particularly among the elderly, who are at greatest risk of severe COVID-19. MethodsWe assessed SARS-CoV-2 humoral responses pre-vaccine and one month following the first dose of BNT162b2 mRNA vaccine, in 12 COVID-19 seronegative residents of long-term care facilities (median age, 82 years), 18 seronegative healthcare workers (HCW; median age, 36 years) and 4 convalescent HCW. Total antibody responses to SARS-CoV-2 nucleocapsid (N) and spike protein receptor binding domain (S/RBD) were assessed using commercial immunoassays. We quantified IgG and IgM responses to S/RBD and determined the ability of antibodies to block S/RBD binding to ACE2 receptor using ELISA. Neutralizing antibody activity was also assessed using pseudovirus and live SARS-CoV-2. ResultsAfter one vaccine dose, binding antibodies against S/RBD were [~]4-fold lower in residents compared to HCW (p<0.001). Inhibition of ACE2 binding was 3-fold lower in residents compared to HCW (p=0.01) and pseudovirus neutralizing activity was 2-fold lower (p=0.003).While six (33%) seronegative HCW neutralized live SARS-CoV-2, only one (8%) resident did (p=0.19). In contrast, convalescent HCW displayed 7- to 20-fold higher levels of binding antibodies and substantial ability to neutralize live virus after one dose. InterpretationExtending the interval between COVID-19 vaccine doses may pose a risk to the elderly due to lower vaccine immunogenicity in this group. We recommend that second doses not be delayed in elderly individuals.