Health Characteristics Associated With Persistence of SARS-CoV-2 Antibody Responses After Repeated Vaccinations in Older Persons Over Time: The Doetinchem Cohort Study

doi:10.21203/rs.3.rs-4888786/v1

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Research Article

Health Characteristics Associated With Persistence of SARS-CoV-2 Antibody Responses After Repeated Vaccinations in Older Persons Over Time: The Doetinchem Cohort Study

https://doi.org/10.21203/rs.3.rs-4888786/v1

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published 15 Oct, 2024

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Background: Older persons elicit heterogeneous antibody responses to vaccinations that generally are lower than those in younger, healthier individuals. As older age and certain comorbidities can influence these responses we aimed to identify health-related variables associated with antibody responses after repeated SARS-CoV-2 vaccinations and its persistence thereafter in SARS-CoV-2 infection-naïve and previously infected older persons.
Method: In a large longitudinal study of older persons of the general population 50 years and over, a sub-cohort of the longitudinal Doetinchem cohort study (n=1374), we measured antibody concentrations in serum to SARS-CoV-2 Spike protein (S1) and Nucleoprotein (N). Samples were taken following primary vaccination with BNT162b2 or AZD1222, and pre- and post-vaccination with a third, fourth BNT162b2 or mRNA-1273 (Wuhan), and a fifth BNT162b2 bivalent (Wuhan/Omicron BA.1) vaccine. Associations between persistence of antibody concentrations over time and age, sex, health characteristics including cardiovascular and inflammatory diseases as well as a frailty index were tested using univariate and multivariate models .
Results: The booster doses substantially increased anti-SARS-CoV-2 Spike S1 (S1) antibody concentrations in older persons against both the Wuhan and Omicron strains. Older age was associated with decreased antibody persistence both after the primary vaccination series and up to 1 year after the fifth vaccine dose. In infection-naïve persons the presence of inflammatory diseases was associated with an increased antibody response to the third vaccine dose (Beta = 1.53) but was also associated with reduced persistence over the 12 months following the fifth (bivalent) vaccine dose (Beta = -1.7). The presence of cardiovascular disease was associated with reduced antibody persistence following the primary vaccination series (Beta = -1.11), but this was no longer observed after bivalent vaccination.
Conclusion: Although older persons with comorbidities such as inflammatory and cardiovascular diseases responded well to SARS-CoV-2 booster vaccinations, they showed a reduced persistence of these responses. This might indicate that especially these more vulnerable older persons could benefit from repeated booster vaccinations.

Ageing

Comorbidities

Inflammatory diseases

Cardiovascular diseases

Frailty

Antibody responses

Antibody persistence

COVID-19 vaccination

Omicron

As the global population ages, the age-related decline in immune function called immunosenescence becomes increasingly important to understand. This encompasses a multifaceted deterioration of the immune system, involving both the innate and adaptive immune responses (Crooke et al., 2019). These age-related changes in immune functioning lead to a heightened susceptibility to infections and diminished vaccine efficacy in older persons (Goronzy & Weyand, 2013; Pereira et al., 2020; Allen et al., 2020). Older persons are also at increased risk of severe complications when infected. Factors contributing to this increased risk include the prevalence of comorbidities such as cardiovascular or inflammatory diseases and increased overall frailty (Chen et al., 2021).

The SARS-CoV-2 pandemic has further highlighted the importance of studying the vaccine responsiveness in older persons. Given the increased vulnerability of older persons to infections, the vaccinations against SARS-CoV-2 play a crucial role in protecting older persons from severe COVID-19 illness and associated complications, as well as in reducing the risk of getting infected. From February 2021, in the Netherlands various vaccines have been offered to the general population chronologically from older to younger age groups: the mRNA vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna); and the viral-vector based vaccines AZD1222 (AstraZeneca) and ABV66.COV2.S (Janssen).

Booster vaccine doses to SARS-CoV-2 are particularly important for maintaining immunity over time, given the limited persistence of vaccine-induced protection and the continuous emergence of new virus variants. The first booster vaccination was implemented for the general Dutch population starting in December 2021 by employing mRNA vaccines. Because of the emergence of the highly transmissible Omicron variant of concern, a second booster was offered only to vulnerable older adults in March 2022, and a bivalent mRNA vaccine which also included Omicron specific mRNA for the first time was offered as a third booster vaccine to the older population in Autumn 2022. Altogether 3 booster vaccines have been administered to the same population in a relatively short time window.

Studying SARS-CoV-2 antibody responses upon vaccination in older adults, is essential to substantiate subsequent vaccination schedules to be able to protect this high-risk group from severe infection outcomes (Rotshild et al., 2021). One such study in older persons showed that subsequent booster vaccinations had a beneficial effect on maintaining IgG antibody concentrations to SARS-CoV-2 and better prevented severe and fatal COVID-19 disease (Speletas et al., 2023).

We have shown a heterogeneous antibody response after the initial primary SARS-CoV-2 vaccinations amongst older persons in which several aspects of frailty play a role (van den Hoogen et al., 2022; Kuijpers et al., 2023). However, little is known about the relation between the persistence of vaccine induced antibody responses to SARS-CoV-2 and its underlying general health determinants in a general population of older persons. In the current study we assess how health characteristics such as frailty are related to the heterogeneity in antibody responses and persistence thereafter following multiple vaccinations against SARS-CoV-2, up to 1 year post fifth vaccination. Furthermore, we aim to identify determinants affecting these responses while considering the specific vaccine received, infection status, and other health related factors. Identifying potential risks for low antibody responses or decreased antibody persistence might contribute towards more targeted follow up vaccination strategies.

Study population

We used the long-running Doetinchem Cohort Study (DCS) that started in 1987 using a population-based random sample of individuals aged 20–59 who were re-examined every 5 years (Verschuren et al., 2008; Picavet et al., 2017). All 3647 persons aged 50–93 years that still participated at the start of the national SARS-CoV-2 vaccination program were invited to take part in a COVID-19 vaccination study for blood sampling and questionnaires. Almost half (46%), aged 50–93 years, agreed to participate. Participants were included in the study if they planned to receive COVID-19 vaccination or had completed the primary vaccination series. This primary vaccination series was completed following either 2 AZD1222 doses or 2 BNT162b2 doses. Booster doses consisted of either BNT162b2 or mRNA-1273.

A total of 1374 participants had completed their primary vaccination series and were followed over the course of the pandemic at various timepoints as seen in Fig. 1. The starting point of the study was 1 month after the second dose of the primary vaccination series (P2), and participants were followed up prior to the third (booster) dose (Pre-B), 1 month after the third dose (B1), 1 month after the fourth dose (2B1), prior to the bivalent fifth dose (Pre-BV), and 1, 6, and 12 months following the bivalent fifth dose (BV1, BV6, and BV12). During the course of the study some individuals dropped out of the study or failed to submit a sample on time explaining the decreasing cohort size towards the end of the study. In addition following the first booster only people aged 60 years or older received a second booster and participated in the later time points (2B1 up to BV12).

Sample collection

Blood samples and questionnaires were taken at each timepoint. Questionnaires covered demographic factors, COVID-19 vaccination information (specific vaccine used and date of vaccination), and SARS-CoV-2 testing information. Finger-prick blood samples (NL76551.041.21, EudraCT 2021-001976-40 and NL74843.041.20, EudraCT 2020-003620-16) were self-collected in microtubes and returned by mail. In addition venapunction blood samples were collected (NL76719.041.21, EudraCT 2021-002363-22). Serum was isolated from each sample by centrifugation and stored at -80°C until sample measurement.

SARS-CoV-2 IgG antibody response measurement

Immunoglobulin G (IgG) antibody concentrations against Spike (S1) and Nucleoprotein (N) were measured simultaneously using a bead-based assay as previously described (den Hartog et al., 2020). IgG concentrations were calibrated against the International Standard for human anti-SARS-CoV-2 immunoglobulin (20/136 NIBSC standard) and expressed as binding antibody units per milliliter (BAU/ml), the threshold for seropositivity was set at 14.3 BAU/ml for Nucleoprotein as described previously (van den Hoogen et al., 2022). From the bivalent vaccination onwards (Pre-BV to BV12) Omicron BA.1 specific anti-S1 IgG antibodies were also measured in arbitrary units AU/ml by using an in house reference serum.

Measurement of health variables

From 1987 up to this vaccination study all participants were followed up, up to 7 times with 5 year intervals in between. During these follow-up rounds questionnaires were administered and a physical examination took place. Questionnaires included data on demographic and lifestyle factors, general health, comorbidities, and quality of life. The physical examination included measurement of blood pressure, lung function, a cognitive test battery, physical functioning, as well as taking a blood sample for measurement of total- and HDL-cholesterol, and glucose.

The frailty index was calculated, consisting of 36 ‘deficits’ defined based on chronic conditions, cognitive, physical, and psychological functioning all of which were included in previous frailty indexes as described before (Samson et al., 2019). Health deficits were either dichotomized or trichotomized with 0 indicating total absence, 0.5 indicating partial/mild presence, and 1 indicating total presence of a given deficit. The sum of deficits was then divided by the number of deficits included resulting in an index ranging from 0 (completely non-frail) to 1 (completely frail).

In addition to constructing the frailty index we used multiple comorbidities available in the questionnaires conducted to construct the cardiovascular- and inflammatory disease prevalence categories as shown in Table 1. These comorbidities were either self-reported or diagnosed by a physician. Inflammatory disease presence was based on prevalence of gastrointestinal diseases, psoriasis, osteoarthritis, joint inflammation, osteoporosis, and nervous system diseases. Presence of cardiovascular disease was based on presence of diabetes, hypertension, stroke, heart failure, heart infarct, and having received a bypass, balloon dilation, cardiac catheterization, pacemaker, and/or vascular surgery. Having at least one of these comorbidities meant inflammatory- or cardiovascular disease presence was determined as positive whereas not having any of the afore mentioned comorbidities meant no disease presence.

Statistical analysis

The age of the study participants was determined at the sample collection date of the first primary vaccination and was used for all subsequent analyses. IgG concentrations were log-transformed prior to all analyses resulting in approximately normally distributed values. Univariate tests to determine pairwise differences in log-transformed antibody concentrations based on vaccine regimen, 10-year age groups, and sex were performed using a Wilcoxon rank sum test and was corrected for multiple testing using the False Discovery Rate (FDR) method. The IgG kinetics post the bivalent booster (Pre-BV to BV12) were visualized using a slope fitted with a linear regression model.

Next, we distinguished four periods between the vaccinations over time: P2 to Pre-B, Pre-B to B1, Pre-BV to BV1, and BV1 to BV12. For each of these periods we calculated the Log2 Fold-Change (LFC) as measure of the relative change in antibody concentrations between two subsequent timepoints. Multivariate linear regression analyses were used to assess the associations between the relative change in antibody LFC and: overall frailty, cardiometabolic factors such as waist circumference and HDL concentrations, and comorbidities including cardiovascular and inflammatory diseases. Multiple separate models were used in order to prevent the inclusion of too many variable into a single model, thereby reducing the risk of multicollinearity. We selected just HDL cholesterol concentration and waist circumference for inclusion in our regression models since these associated strongly with body mass index (BMI), total cholesterol, systolic blood pressure, creatinine- and glucose concentrations, and estimated glomerular filtration rate (eGFR).

The regression analysis was also corrected for age, sex, the specific vaccine used, and the baseline antibody concentration per period analyzed. This allowed us to assess the effect of the variables of interest on the change in antibody concentrations irrespective of their association with the antibody concentration at the start of a period. The obtained model estimates (Betas) were divided by twice the standard error per variable of interest to normalize their range resulting in the betas reported. All analyses were stratified for infection status as determined based on SARSCoV2 N-seropositivity, positive antigen test, or self-reported COVID-19 infection. All statistical analyses were performed using R version 4.3.0. Statistical significance was defined as p-value ≤ 0.05.

Overview

An overview of the study and the number of older persons in the various vaccination rounds over time can be seen in Fig. 1. Based on a complete primary vaccination series as part of the inclusion criteria and the defined time window for sampling at 1 month post primary vaccination (P2), 1461 participants were included. Of these persons, 1374 had received either two doses of BNT162b2 or two doses of AZD1222 and were included in further SARS-CoV-2 antibody analyses at least at one of the timepoints in this study. Groups were divided in infection naïve and infected persons over time.

General characteristics
The baseline characteristics on demographics, lifestyle, cardiometabolic factors and comorbidities of the men and women that participated in the study are shown Table 1. We also included the frailty index, a summary measure of frailty based on 36 deficits, ranging from 0 (non-frail) to 1 (maximum frail). There were statistically significant differences between men and women for most baseline characteristics, except for current smoking behavior, body mass index (BMI), and inflammatory disease incidence. Men were on average slightly older and showed higher levels of alcohol consumption, a higher waist circumference, higher systolic blood pressure, higher creatine and glucose concentrations, a higher estimated glomerular filtration rate (eGFR) and a higher cardiovascular disease presence, whereas in women higher total and HDL cholesterol concentrations and a higher frailty index was observed.

Table 1: Baseline health characteristics of the study population (N = 1374).

	Men, N = 662	Women, N = 712	P value¹
Sociodemographic
Age (years) (mean (SD²))	69 (7.8)	67 (7.3)	<0.001
Socio-Economic Status (%)			0.001
Low	28	38
Middle	37	31
High	35	31
Lifestyle
Currently smoking (%)	6.2	7.3	0.784
Drinking alcohol (%)	77.6	59.9	<0.001
Cardiometabolic factors
BMI (kg/m2) (mean (SD))	26.7 (3.6)	26.5 (4.8)	0.335
Waist circumference (cm) (mean (SD))	100.8 (10.2)	92.1 (12.7)	<0.001
Systolic blood pressure (mmHg) (mean (SD))	133 (16)	130 (17)	<0.001
Total cholesterol (mmol/L) (mean (SD))	5.1 (1.0)	5.6 (1.0)	<0.001
HDL cholesterol (mmol/L) (mean (SD))	1.3 (0.3)	1.6 (0.4)	<0.001
Creatinine (mmol/L) (mean (SD))	92.0 (18.3)	72.9 (11.8)	<0.001
Glucose (mmol/L) (mean (SD))	5.9 (1.7)	5.6 (1.4)	<0.001
Comorbidity related factors
eGFR (mean (SD))	1.0 (0.3)	0.9 (0.2)	<0.001
Frailty index (median [IQR³])	0.05 [0.02, 0.09]	0.07 [0.03, 0.12]	<0.001
Inflammatory disease presence⁴ (%)	12.4	14.0	0.409
Cardiovascular disease presence⁵ (%)	53.9	46.1	0.004

1: P values indicating sex differences were generated using a t-test or Fisher’s exact test for continuous and categorical variables respectively

2: SD = standard deviation

3: IQR = interquartile range

4: Gastrointestinal diseases, Psoriasis, Osteoarthritis, Joint inflammation, Osteoporosis, Nervous system diseases
5: Diabetes, Hypertension, Stroke, Heart failure, Heart infarct, Bypass, Balloon dilation, Cardiac catheterization, Pacemaker, Vascular surgery

SARS-CoV-2 anti-S1 IgG antibody responses over time, stratified by infection status and sex
At 1 month after the primary vaccination series (P2) the persons vaccinated with two doses of AZD1222 showed a lower antibody concentration compared to those vaccinated with BNT162b2 (Fig. 2A). This was statistically significant for both previously infected and infection naïve individuals (Wilcoxon rank sum test P-value < 0.0001, Supplementary Table S1). After subsequent boosters this initial difference based on the primary vaccination series seemingly disappeared in infection naïve individuals following the bivalent booster vaccination. Generally, all persons, both with and without prior infection, and those vaccinated with either BNT162b2 or AZD1222 for their two primary vaccination doses, showed a similar pattern for their antibody responses over the various timepoints after the booster vaccinations (fig 2A, Supplementary Table S1)

After stratifying by 10-year age groups (fig. 2B), we observed that the antibody concentrations after primary vaccination at P2 and prior to the first booster at B0 appeared lower in older age groups compared to younger ones showing significant differences between the 50 – 59 year old vaccinee’s compared to the 80 -89 year old vaccinee’s (P < 0.05, Supplementary Table S2). In both previously infected individuals and infection naïve individuals these age related differences largely disappeared later in time after continued vaccination with either BNT162b2 or mRNA-1273 booster vaccines.

Omicron BA.1 specific anti SARS-CoV-2-S1 IgG antibody responses were measured prior to bivalent vaccination (fifth vaccine dose) (Pre-BV) and 1, 6, and 12 months following bivalent vaccination (BV1, BV6, BV12) (Supplementary Figure S1). There was a notable increase in Omicron specific anti-S1 IgG concentrations 1 month after bivalent vaccination (BV1). There were no differences in these antibody concentrations between males and females (Supplementary Table S3) or between various age groups (Supplementary Table S4) at any given time point.

Anti-S1 IgG antibody response and persistence of antibody levels following bivalent vaccination
In the first month following bivalent booster vaccination both infection naïve persons and those with a prior infection showed a strong increase in their Wuhan strain SARS-CoV-2 anti-S1 IgG antibody concentrations followed by a slight decline after a year post vaccination (fig. 3A). Persons with a prior infection had a higher antibody concentration prior to vaccination and 1 month after vaccination. Both infection-naïve and previously infected persons experienced an increase in antibody concentrations after receiving a bivalent vaccination as indicated by the slope (Beta = 0.57, 0.55 in infection-naïve women and men respectively, and Beta = 0.38, 0.39 in infected women and men respectively). We observed no effect of sex or infection status on the slope of the antibody persistence during the year following bivalent vaccination (Beta = -0.03, -0.04 in infection-naïve women and men respectively, and Beta = -0.03, in both infected women and men).

Omicron BA.1 specific anti-S1 IgG responses over the same period showed a similar pattern as found for the Wuhan strain anti-S1 IgG responses but with a stronger increase at 1 month post vaccination, as can be seen in figure 3B. We observed an increase upon vaccination for the Omicron BA.1 specific anti-S1 IgG antibodies (Beta = 0.68 and 0.66 for infection-naïve women and men respectively, and Beta = 0.52 and 0.56 for infected women and men respectively) followed by the waning of antibodies over time (Beta = -0.04 and 0,05 for infection-naïve women and men respectively, and Beta = -0.04 for both infected women and men).

Associations between age, sex, and persons health characteristics with SARS-CoV-2 IgG responses over time.
Multivariate regression analysis (Fig. 4) showed a significant effect of the type of vaccine used in the primary vaccination series on the antibody persistence post second vaccination (P2 – Pre-B). Figure 4A shows that persons that received two BNT162b2 doses had a stronger decrease compared to those vaccinated with AZD1222 (Beta = -1.23 for infection-naïve persons and Beta = -1.71 for previously infected persons). Furthermore, within the infected group a higher frailty index was associated with a stronger decline in IgG concentrations (Beta = -1.36).

In the month following the first booster vaccination (with a third vaccine dose) (Pre-B – B1), no significant association was found between the fold increase in antibody concentrations and the type of primary vaccinations. However, both infection-naïve and previously infected persons receiving a BNT162b2 vaccine as their first booster showed a significantly lower increase in IgG concentrations compared to those who received an mRNA-1273 booster vaccine (Beta = -1.19 for infection-naïve persons and Beta = -1.13 for previously infected persons). After the subsequent booster vaccinations, no significant differences were observed in antibody responses between the received vaccine types. In the period after the fifth (bivalent) vaccination dose (BV1 – BV12) the persistence of antibodies was negatively associated with age, in just the infection-naïve persons (Beta = -1.31) (Fig.4A)

We observed that during the month following the third vaccine dose (Pre-B – B1), HDL cholesterol concentrations were associated with a reduced increase in IgG concentrations in infection-naïve persons (Beta = -1.56) (Fig. 4B). During the one-year period following bivalent vaccination (BV1 – BV12) a positive association between HDL and antibody concentrations (Beta = 1.24) was observed in these persons. This means that those with higher HDL concentrations experienced an increased antibody persistence one year post bivalent vaccination. No associations were found between waist circumference and changes in antibody concentrations during any of the periods (Fig.4B)

Lastly we observed that persons suffering from cardiovascular diseases experienced a stronger decline (Beta = -1.11) in IgG concentrations following the primary vaccination series (P2 – Pre-B) (fig. 4C). Persons suffering from inflammatory diseases experienced a stronger increase (Beta = 1.53) in IgG concentrations in response to the third vaccine dose (Pre-B – B1). However, after 1 year following bivalent vaccination (BV1 – BV12), the presence of an inflammatory disease was associated with a stronger decrease in antibody levels for both infection-naïve persons (Beta = -1.7) and previously infected persons (Beta = -1.0) (Fig. 4C).

Associations between baseline health characteristics, comorbidities and Omicron specific antibody responses
Following bivalent vaccination we observed that those with a higher baseline anti-S1 IgG concentration experience a relatively smaller increase 1 month after bivalent vaccination (Pre-BV – BV1) (infection naïve Beta = -4.01; infected Beta = -3.75). Infection-naïve persons who had previously received a BNT162b2 booster vaccine as opposed to a mRNA-1273 experienced a slightly higher increase in antibody concentration upon bivalent vaccination (Beta = 1.08). In addition we foundthat in previously infected persons a higher baseline anti-S1 IgG concentration was associated with a stronger decline in antibody concentration (Beta = -2.8) during the year following bivalent vaccination (BV1 – BV12) (fig. S2A). During the year following bivalent vaccination women retained higher antibody concentrations compared to men (Beta = 1.03) in infection-naïve persons (fig. S2A). During the same period HDL concentrations were also associated with a higher antibody persistence (Beta = 1.13) in infection-naïve persons (fig. S2B). Lastly, the presence of inflammatory disease was associated with a reduced persistence of antibody concentrations during this period for both infection-naïve (Beta = -1.79) and previously infected persons (Beta = -1.07) (fig. S2C).

In this study we explored whether various health characteristics are related to the persistence of SARS-CoV-2 antibody responses of older men and women from the general population following five SARS-CoV-2 vaccinations over time. Overall the three booster mRNA vaccines over time substantially increased anti-SARS-CoV-2 Spike S1 (S1) antibody concentrations in older persons. However, ageing was associated with decreased antibody persistence both after the primary vaccination series and up to 1 year after the fifth vaccine dose. Although older persons showing comorbidities such as inflammatory diseases and cardiovascular diseases also responded well to SARS-CoV-2 booster vaccinations, they showed a reduced persistence of these responses.

Previously we have shown that uninfected frailer persons experienced a reduced SARS-CoV-2 antibody response upon primary vaccination while those suffering from cardiovascular diseases had an increased antibody response (Kuijpers et al., 2023). In contrast, in the current study we observed that infection-naïve persons with cardiovascular disease experienced a stronger waning of their antibody concentrations. Also, in previously infected persons, frailty was associated with a stronger decrease in antibody concentrations during the same period. These results were in agreement with the positive association between antibody responses and cardiovascular diseases followed by a faster waning of antibody concentrations afterwards reported before (Karachaliou et al., 2022). The relation between comorbidities and frailty in older persons and a weakened immunity has been reported extensively (Jia et al., 2022), highlighting the role of frailty in reduced antibody responses to vaccination in older persons (Allen et al., 2020). However, our study showed that after a fifth SARS-CoV-2 vaccine dose with a bivalent vaccine the differences in antibody responses and persistence over time between frail and less frail individuals, or those with and without cardiovascular diseases, are no longer present. We did however observe that infection-naïve persons with higher HDL cholesterol concentrations had an increased antibody persistence after bivalent vaccination. Because of the association between HDL cholesterol concentrations, and other cardiometabolic factors, the cause could be multifactorial, even related to medication use (Wildes et al., 2019).

Additionally, we observed that the presence of inflammatory diseases was associated with a stronger increase of antibody response to the third vaccination. This finding is especially of interest given that previous studies in contrast have found that these patient groups experience a lower magnitude and faster waning of antibody responses upon vaccination (Garner-Spitzer et al., 2023). However, these patients are often treated with anti-inflammatory therapeutics that could inhibit the antibody response by inhibiting the cytokine response or inhibiting immune cells, which could explain this association (van Sleen et al., 2023). Other studies have linked a short interruption of anti-inflammatory treatment with an increased antibody response after vaccination compared to patients receiving continued treatment (Abhishek et al., 2024). Based on our findings, older persons with inflammatory diseases may experience a stronger antibody response after a booster vaccination compared to relatively healthy older persons, though this group also showed a decreased antibody persistence during the 12 months following bivalent vaccination with a fifth vaccine dose. In addition, the waning of antibody concentrations over time after vaccination has been linked to increased COVID-19 mortality in frail nursing home residents (Vikström et al., 2023). This indicates that while vulnerable older people might initially induce a strong antibody response upon the first booster vaccination, there remains a need for surveillance of immunity and repeated booster vaccinations over time to maintain SARS-CoV-2 antibody levels.

Our study showed that with increasing age, antibody levels had decreased more at 6–8 months after the primary vaccinations just before the first booster. A similar association between age and antibody waning was observed during the 12 months following the fifth vaccine dose in infection-naïve participants. We also observed that women experienced a stronger increase in antibody concentrations after their first booster vaccination compared to men in infection-naïve persons that was not observed after bivalent vaccination. Sex differences have been reported before with regards to the antibody response upon SARS-CoV-2 vaccination (Kuijpers et al., 2023; Fernandes et al., 2023). Other studies focusing on antibody persistence after just a third SARC-CoV2 vaccine dose in older persons did not observe sex differences anymore, but did find that different comorbidities affected the antibody persistence depending on sex (Trevisan et al., 2023). We however observed that at least 12 months after bivalent vaccination infection-naïve women still have a higher antibody persistence for Omicron BA.1 specific anti-S1 IgG antibodies than men. This might be explained by the primary vaccine responses to the Omicron virus strain in this infection naïve group of persons .

Previous studies have shown that after infection elevated antibody concentrations can still be observed up to 9 months after recovering. Those with asymptomatic disease however showed a lower persistence of the antibody response (Carvalho et al., 2023). A similar pattern based on infection severity was seen in unvaccinated hospitalized patients (de Oliveira et al., 2024), as well as in vaccinated older persons using neutralizing antibodies (Hansen et al., 2023). We however observed a strong decline in IgG antibody concentrations approximately 6 months after the second vaccine dose in both infection-naïve and previously infected persons leading up to the first booster vaccination. This decrease in antibody concentrations following the primary vaccination series has previously also been linked to a decline in infection protection (Fiolet et al., 2022). After the first booster vaccination (third vaccine dose) antibody concentrations showed a substantial increase irrespective of infection status and the vaccine used for the primary vaccination series. This substantial increase in antibody responses after the first SAR-CoV-2 booster dose has been reported by others as well even for older nursing home residents (Naaber et al., 2021; Bruel et al., 2022; Fedele et al., 2022; Jeulin et al., 2022). After vaccination with two subsequent additional booster doses we consistently observed increases in antibody concentrations 1 month after vaccination. The waning of antibody concentrations after the bivalent vaccine as the fifth vaccine dose was not as steep as seen after the primary vaccination series. This was corroborated by other longitudinal studies though these study populations included younger adults as well (Matsumoto et al., 2024). We observed a relatively stronger increase in Omicron BA.1 specific antibody concentrations after bivalent vaccination than those observed for Wuhan specific antibody concentrations. Although this was the first Omicron BA.1 specific immunization, antibody concentrations persisted up to one year post vaccination in infection naïve individuals, that was in contrast to the relatively fast waning of antibodies after the primary vaccination series. This might be explained by cross-reactive antibodies immunity induced by the Wuhan-strain specific vaccines and the Omicron BA.1 strain which is in accordance with other studies (Cheng et al., 2024). The ability of bivalent boosters to generate a broad and strong antibody response has been noted previously with regards to the importance to continuously adapt the SARS-CoV-2 vaccines to protect against new strains (Chalkias et al., 2024).

In our study about 75% of the participants received dual BNT162b2 vaccinations and 25% (aged 51–68 years) received dual AZD1222 vaccinations. Following these primary vaccination series antibody concentrations of AZD1222 vaccinee’s waned significantly slower than those in persons vaccinated with BNT162b2. These persons however, showed a relatively weaker antibody persistence afterwards than those vaccinated with AZD1222, possibly due to the lower initial antibody response in those vaccinated with AZD1222 and a better induction of B-cell maturation as reported previously (Ward et al., 2022). In addition, others have shown a slightly better humoral response for heterologous vaccination after the first booster dose (Atmar et al., 2022). However, we showed that after subsequent mRNA booster vaccinations in time any possible difference in antibody persistence following BNT162b2 or AZD1222 as the primary vaccination series was no longer observed.

Using all longitudinal data of our preexisting large cohort we were able to accurately detect the presence of comorbidities and other health related factors known prior to the COVID-19 pandemic. The extensive collection of data also allowed us to construct multiple variables such as the frailty index and the presence of inflammatory- and cardiovascular diseases. This allowed us to assess the effects of frailty and specific health characteristics on the antibody responses after multiple subsequent SARS-CoV-2 vaccinations and the persistence of these antibodies during 2,5 years follow up longitudinally. Moreover, we measured Omicron BA.1 specific anti S1 antibody responses post bivalent vaccination separately from that of the Wuhan strain and antibodies specific to the SARS-CoV-2 nucleocapsid (N) protein to distinguish infection naïve and infected persons over time.

However, due to the low number of infection-naïve persons towards the end of study, analyses in this subgroup had less power which could partly explain the lack of significant associations with the presence of comorbidities in these analyses and the persistence of antibodies. In addition, to prevent multicollinearity due to a smaller cohort size over time combined with the high number of health variables we had to combine multiple variables in order to accurately assess the effects of these health characteristics on the antibody responses.

In summary, our study contributes to the surveillance of the vaccine induced antibody responses against SARS-CoV-2 over the course of the Corona virus pandemic, emphasizing the role of booster vaccination doses in older vulnerable persons for maintaining antibody concentrations. We identified that older age was associated with reduced antibody persistence but only in infection-naïve individuals. Furthermore, we identified potential risk groups within the older population such as those having inflammatory diseases and cardiovascular diseases that have a reduced antibody response or persistence of antibody concentrations over time. These more vulnerable groups of older persons especially might benefit from further SARS-CoV-2 booster vaccinations.

Ethics approval and consent to participate
The study was conducted according to the principles of the World Medical Association Declaration of Helsinki and its amendments since 1964 , and in accordance with the Medical Research Involving Human Subject Act (WMO). The study protocols were approved by the Medical Ethics Committee of the University Medical Center Utrecht and all informed consent was obtained from all participants. Ethical approval was for finger prick blood sampling in the majority of the DCS participants (NL76551.041.21, EudraCT 2021-001976-40) and for finger prick blood sampling as well as venapunction in a small part of the participants (NL74843.041.20, EudraCT 2020-003620-16 and NL76719.041.21, EudraCT 2021-002363-22).

Consent for publication
Not applicable.

Competing interests
The authors declare no competing interests.

Funding
This work was supported by the Dutch Ministry of Public Health, Welfare, and Sports (VWS).

Authors’ contributions
The study was conceptualized and designed by H.S.J.P., J.K., W.M.M.V., and A.B. Analysis was performed by Y.K. with input from by H.S.J.P., J.K., W.M.M.V., and A.B. MZB, MK and LR: data investigation, data curation and writing editing. IS. EG and RR, clinical study and data management. The manuscript was written by Y.K. with input from all authors. All authors read and approved the final manuscript.

Acknowledgements
We would like to thank all members of the Doetinchem Cohort Study and those that participated in the SARS-CoV-2 vaccination study. We would also like to thank Peter Engelfriet for his help in designing and conceptualizing the study, as well as Marjan Bogaard, Kim Nijhof, Vera Selhorst, Joyce Greeber, Petra Molenaar, Inge Pronk, Gaby Smit, and Irene Middelhof for additional help with the sample collections and antibody measurements.

Availability of data and materials
We welcome collaboration. For use of the available data, please contact Professor W. M. M. Verschuren or H. S. J. Picavet, PhD (doetinchemstudie [at] rivm [dot] nl).

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Health Characteristics Associated With Persistence of SARS-CoV-2 Antibody Responses After Repeated Vaccinations in Older Persons Over Time: The Doetinchem Cohort Study

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SARS-CoV-2 IgG antibody response measurement

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