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

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.

Characterization of the significant decline in humoral immune response six months post-SARS-CoV-2 mRNA vaccination: A systematic review

Accumulating evidence shows a progressive decline in the efficacy of coronavirus disease 2019 (COVID-19) mRNA vaccines such as Pfizer-BioNTech (mRNA BNT161b2) and Moderna (mRNA-1273) in preventing breakthrough infections due to diminishing humoral immunity over time. Thus, this review characterizes the kinetics of anti-SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) antibodies after the second dose of a primary cycle of COVID-19 mRNA vaccination. A systematic search of literature was performed and a total of 18 studies (N=15,980) were identified and reviewed. The percent difference of means of reported antibody titers were then calculated to determine the decline in humoral response after the peak levels post-vaccination. Findings revealed that the peak humoral response was reached at 21-28 days after the second dose, after which serum levels progressively diminished at 4-6 months post-vaccination. Additionally, results showed that regardless of age, sex, serostatus and presence of comorbidities, longitudinal data reporting antibody measurement exhibited a decline of both anti-receptor binding domain (RBD) IgG and anti-spike IgG, ranging from 94-95% at 90-180 days and 55-85% at 140-160 days, respectively, after the peak antibody response. This suggests that the rate of antibody decline may be independent of patient-related factors and peak antibody titers but mainly a function of time and antibody class/molecular target. Hence, this study highlights the necessity of more efficient vaccination strategies to provide booster administration in attenuating the effects of waning immunity, especially in the appearance of new variants of concerns (VoCs).

Seroprevalence in Tamil Nadu through India's two COVID waves: Evidence on antibody decline following infection and vaccination

Three rounds of population-representative serological studies through India's two COVID waves (round 1, 19 October-30 November 2020; round 2, 7-30 April 2021; and round 3, 28 June-7 July, 2021) were conducted at the district-level in Tamil Nadu state (population 72 million). State-level seroprevalence in rounds 1, 2 and 3 were 31.5%, 22.9%, and 67.1%. Estimated seroprevalence implies that at least 22.6 and 48.1 million persons were infected by the 30 November 2020 and 7 July 2021. There was substantial variation across districts in the state in each round. Seroprevalence ranged from 11.1 to 49.8% (round 1), 7.9 to 50.3% (round 2), and 37.8 to 84% (round 3). Seroprevalence in urban areas was higher than in rural areas (35.7 v. 25.7% in round 1, 74.8% v. 64.1% in round 3). Females had similar seroprevalence to males (30.8 v. 30.2% in round 1, 67.5 v. 65.5% in round 3). While working age populations (age 40-49: 31.6%) had significantly higher seroprevalence than the youth (age 18-29: 30.4%) or elderly (age 70+: 26.5%) in round 1, only the gap between working age (age 40-49: 66.7%) and elderly (age 70+: 59.6%) remained significant in round 3. Seroprevalence was greater among those who were vaccinated for COVID (25.7% v. 20.9% in round 2, 80.0% v. 62.3% in round 3). While the decline in seroprevalence from rounds 1 to 2 suggests antibody decline after natural infection, we do not find a significant decline in antibodies among those receiving at least 1 dose of COVID vaccine between rounds 2 and 3.

Assessing antibody decline after chemotherapy of early chronic Chagas disease patients

Background Chagas disease remains a significant public health problem in Latin America. There are only two chemotherapy drugs, nifurtimox and benznidazole, and both may have severe side effects. After complete chemotherapy of acute cases, seropositive diagnosis may revert to negative. However, there are no definitive parasitological or serological biomarkers of cure. Methods Following a pilot study with seven Bolivian migrants to Spain, we tested 71 serum samples from chronic patients (mean age 12.6 years) inhabiting the Argentine Chaco region. Benznidazole chemotherapy (5–8 mg/kg day, twice daily for 60 days) was administered during 2011–2016. Subsequently, pre-and post-chemotherapy serum samples were analysed in pairs by IgG1 and IgG ELISA using two different antigens and Chagas Sero K-SeT rapid diagnostic tests (RDT). Molecular diagnosis by kDNA-PCR was applied to post-treatment samples. Results Pilot data demonstrated IgG1 antibody decline in three of seven patients from Bolivia 1 year post-treatment. All Argentine patients in 2017 (averaging 5 years post-treatment), except one, were positive by conventional serology. All were kDNA-PCR-negative. Most (91.5%) pre-treatment samples were positive by the Chagas Sero K-SeT RDT, confirming the predominance of TcII/V/VI. IgG1 and IgG of Argentine patients showed significant decline in antibody titres post-chemotherapy, with either lysate (IgG, P = 0.0001, IgG1, P = 0.0001) or TcII/V/VI peptide antigen (IgG, P = 0.0001, IgG1, P = 0.0001). IgG1 decline was more discriminative than IgG. Antibody decline after treatment was also detected by the RDT. Incomplete treatment was associated with high IgG1 post-treatment titres against lysate (P = 0.013), as were IgG post-treatment titres to TcII/V/VI peptide (P = 0.0001). High pre-treatment IgG1 with lysate was associated with Qom ethnicity (P = 0.045). No associations were found between gender, age, body mass index and pre- or post-treatment antibody titres. Conclusions We show that following chemotherapy of early chronic Chagas disease, significant decline in IgG1 antibody suggests cure, whereas sustained or increased IgG1 is a potential indicator of treatment failure. Due to restricted sensitivity, IgG1 should not be used as a diagnostic marker but has promise, with further development, as a biomarker of cure. Graphical abstract We show that following chemotherapy of early chronic Chagas disease, a significant decline in IgG1 antibody suggests cure, whereas sustained or increased IgG1 is a potential indicator of treatment failure. Due to restricted sensitivity, IgG1 should not be used as a diagnostic marker but has promise, with further development, as a biomarker of cure.

Waning of IgG, Total and Neutralizing Antibodies 6 Months Post-Vaccination with BNT162b2 in Healthcare Workers

Data about the long-term duration of antibodies after SARS-CoV-2 vaccination are still scarce and are important to design vaccination strategies. In this study, 231 healthcare professionals received the two-dose regimen of BNT162b2. Of these, 158 were seronegative and 73 were seropositive at baseline. Samples were collected at several time points. The neutralizing antibodies (NAbs) and antibodies against the nucleocapsid and the spike protein of SARS-CoV-2 were measured. At day 180, a significant antibody decline was observed in seronegative (−55.4% with total antibody assay; −89.6% with IgG assay) and seropositive individuals (−74.8% with total antibody assay; −79.4% with IgG assay). The estimated half-life of IgG from the peak humoral response was 21 days (95% CI: 13–65) in seronegative and 53 days (95% CI: 40–79) in seropositive individuals. The estimated half-life of total antibodies was longer and ranged from 68 days (95% CI: 54–90) to 114 days (95% CI: 87–167) in seropositive and seronegative individuals, respectively. The decline of NAbs was more pronounced (−98.6%) and around 45% of the subjects tested were negative at day 180. Whether this decrease correlates with an equivalent drop in the clinical effectiveness against the virus would require appropriate clinical studies.

Waning of IgG, total and neutralizing antibodies 6 months post-vaccination with BNT162b2 in healthcare workers

Data about the duration of humoral response following COVID-19 vaccines are mandatory to establish appropriate population vaccination strategy. This study reports on the antibody decline observed in a population of COVID-19 naïve and COVID-19 positive individuals having received the two dose regimen of the BNT162b2 vaccine. Six months after vaccination, a significant antibody decline was observed in both COVID-19 naïve and positive individuals. The estimated half-life of total and IgG antibodies differs and ranges from several months for total antibodies to only several weeks for IgG antibodies, explaining the significant proportions of participants with non-detectable levels of neutralizing antibodies at 6 months. Whether this decrease correlates with an equivalent drop in the clinical effectiveness against the virus will require appropriate clinical studies. Nevertheless, these data are already important to support the decision-making on the potential use of a booster dose.

Antibody titers decline 3-month post-vaccination with BNT612b2

Introduction: Several studies reported on the humoral response in subjects having received theBNT162b2 mRNA COVID-19 vaccine. However, data on the kinetics of antibodies 3 months postvaccinationare currently lacking and are important to drive the future vaccination strategy.Methods: The CRO-VAX HCP study is an ongoing multicenter, prospective and interventional studydesigned to assess the antibody response in a population of healthcare professionals who had receivedtwo doses of the BNT162b2 mRNA COVID-19 vaccine. Two-hundred individuals underwent a blooddrawn within 2 days before the first vaccine dose. One-hundred and forty-two persons (71%) werecategorized as seronegative at baseline while 58 (29%) were seropositive. Samples were then collectedafter 14, 28, 42, 56, and 90 days. Antibodies against the SARS-CoV-2 nucleocapsid and the receptorbinding domain of the S1 subunit of the spike protein were measured in all individuals at different timepoints.Results: Using a one-compartment kinetics model, the time to maximum concentration was estimatedat 36 ± 3 days after the first dose and the estimated half-life of antibodies was 55 days (95% CI: 37-107days) in seronegative participants. In seropositive participants, the time to maximum concentrationwas estimated at 24 ± 4 days and the estimated half-life was 80 days (95% CI: 46-303 days). Theantibody response was higher in seropositive compared to seronegative participants.Conclusion: In both seropositive and seronegative subjects, a significant antibody decline wasobserved at 3 months compared to the peak response. Nevertheless, the humoral response remainedrobust in all participants.

SARS-CoV-2 seroprevalence survey estimates are affected by anti-nucleocapsid antibody decline

We analyzed 21,676 residual specimens from Ontario, Canada collected between March-August, 2020 to investigate the effect of antibody decline on SARS-CoV-2 seroprevalence estimates. Testing specimens orthogonally using the Abbott (anti-nucleocapsid) and then the Ortho (anti-spike) assays, seroprevalence estimates ranged from 0.4%-1.4%, despite ongoing disease activity. The geometric mean concentration (GMC) of antibody-positive specimens decreased over time (p=0.015), and the GMC of antibody-negative specimens increased over time (p=0.0018). The association between the two tests decreased each month (p&lt;0.001), suggesting anti-N antibody decline. Lowering the Abbott antibody index cut-off from 1.4 to 0.7 resulted in a 16% increase in positive specimens.