Abstract
The first two vaccines administered in the COVID-19 vaccination campaign of India were Covaxin (BBV152) and Covishield (ChAdOx1-nCoV-19). In this study, we evaluate the longevity and sustainability of the humoral immune response after vaccination and various factors influencing it. An observational study was conducted in individuals who received both doses of Covaxin or Covishield vaccine, and their blood samples were analyzed for total-antiRBD-SARS-CoV-2 antibodies. Then, antibody titers were classified based on monthly time-intervals up to 360 days and their trend was analyzed. In addition, the correlation between antibody titers and factors such as previous SARS-CoV-2-infection status, vaccine type and presence of comorbidities was examined. Of the 2069 participants, most (1767;85.4%) had been vaccinated with Covaxin, but the higher antibody titers were induced by Covishield vaccine at all time points. However overall, antibodies persisted for at least 1 year, although a drop in antibody titers occurred in the 3rd and 6th months. In addition, 430 (20.8%) participants had prior SARS-CoV-2 infection (hybrid immunity) with a significantly higher humoral immune response compared with vaccine-induced immunity (naive immunity). No significant differences were observed in antibody titers related to age, sex and presence of comorbidities. We concluded that vaccine-mediated immunity lasts for at least one year. However, antibody titers decrease over time, which may be more pronounced in certain groups such as Covaxin vaccine, vaccine-induced-immunity, presence of comorbidities and > 60 years which should be considered when recommending booster vaccination, as these individuals may have a stronger and longer-lasting immune response to the virus.
Keywords: SARS-COV-2 antibodies, COVID-19, Persistence, Covaxin, Covishield
Introduction
The ongoing coronavirus disease 2019 (COVID-19) pandemic had a tremendous impact on both health and finances globally. To curb it, the COVID-19 vaccine drive in India was launched on January 16, 2021 [1]. Two vaccines have been approved in India: Covishield, which is manufactured by the Serum Institute of India and is based on a weakened version of a common cold virus called ChAdOx1 nCoV-19, and Covaxin, which is made by Bharat Biotech and is an inactivated whole virion SARS-CoV-2 antigen [2]. Both vaccines target the receptor-binding domain (RBD) of the spike (S) glycoprotein of the SARS-CoV-2 virus to induce neutralizing antibodies to reduce overall mortality. Initially, both doses of Covishield were administered 28 days apart, but the interval was later increased to 84 days [3, 4]. Whereas for Covaxin, both doses are administered at a gap of 28 days [5]. Phase 3 trials of Covaxin and Covishield reported efficacies of 77.8% and 81% respectively [6, 7]. As of January 16, 2022, 1.56 billion vaccine doses have been administered globally [8].
The aim of these vaccines is to stimulate the production of neutralizing antibodies by introducing harmless virus components, like the spike protein, to the immune system. This exposure trained the immune system to identify and respond to the virus if encountered afterward. This approach aimed to achieve herd immunity, potentially leading to disease eradication. Herd immunity is when a significant portion of the population is immune to a disease through vaccination or natural infection, curbing virus transmission. Nevertheless, for COVID-19, classical herd immunity might not have been reached, as the longevity of vaccine- or infection-induced immunity to SARS-CoV-2 is short lived and the emergence of escape mutants could have perpetuated viral spread, albeit ideally at a low endemic level [9, 10].
The emergence of various variants of concern (VoCs) such as alpha (B.1.1.17), delta (B.1.617.2), and omicron (B.1.1.529) has led to breakthrough infections and COVID-19 waves in January 2021, April 2021, and January 2022 respectively. Studies have also shown that antibodies developed against SARS-CoV-2 following natural infection and/or vaccination may wane over time [11, 12]. With the rise of newer virus variants and the possibility of reinfection, it is important to critically assess the persistence of antibodies after vaccination to ensure immunity against future infections.
The study aimed to evaluate the persistence of anti-RBD SARS-CoV-2 total antibodies after COVID-19 vaccination, and to assess the correlation of these antibodies with factors such as age, gender, comorbidities, vaccine type, and prior natural COVID-19 infection.
Methodology
This cross-sectional observational study was carried out at the All India Institute of Medical Sciences, New Delhi, and its affiliated centers from March 2021 to January 2022.
Ethical Approval
The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki. The approval of the Institutional Ethical Committee (AIIMS, New Delhi) was obtained before initiating the study (IEC-181/05.03.2021, RP-10/2021). Informed consent was obtained from the participants.
Participant Enrollment and Data Collection
All the participants receiving COVID-19 vaccination at AIIMS, New Delhi were eligible to participate in serology testing voluntarily by filling up an online test requisition and consent form. The form included demographic information, designation, type of vaccine, dates of first and second doses, COVID-19 infectivity status, dates of positivity and reinfection, and information on comorbidities. Participants who did not consent, or who had received only one dose of the vaccine, were excluded. Also, samples from participants who acquired COVID-19 infections after completing their vaccinations were also excluded. The data was collected and stored in a password-protected online database.
As the prevalence of SARS-CoV-2 antibody in the Indian population is not known, it was assumed to be 50%. With 95% confidence level and 2.2% margin of error, 1985 (Rounding off to 2000) will be recruited for the present study.
SARS-CoV-2 Antibodies Measurement
In this study 2 ml of venous blood was collected in a serum separator tube under aseptic conditions, and processed for the total antibody (including IgG and IgM) SARS-CoV-2 assay, using the ADVIA Centaur COV2T assay (Siemens AG, Munich, Germany) in the ADVIA Centaur XPT (Siemens AG, Munich, Germany) at the Robotic Core Clinical Laboratory, National Cancer Institute (NCI)-Jhajjar, AIIMS. The assay was performed according to the manufacturer's protocol and institutional infection control guidelines. It is a fully automated one-step antigen sandwich immunoassay that uses acridinium ester chemiluminescence technology and detects the antibody to spike protein receptor binding domain (S1RBD) on the surface of the SARS-CoV-2 virus. The spike protein binds the virus to the target cells by a distinct human receptor (ACE2) found in the lung, heart, multiple organs and blood vessels. There is a direct relationship between the amount of SARS-CoV-2 antibodies present in the sample and the amount of relative light units (RLUs) detected by the system. The result of reactive (≥ 1) or nonreactive (< 1) is determined according to the Index value established with the calibrators.
Study Design
Anti-RBD SARS-CoV-2 total antibody titers after the second dose of SARS-CoV-2 vaccine from included participants were classified based on time intervals as T0 (≤ 14 days), T1 (14–30 days), T2 (31–60 days), T3 (61–90 days), T4 (91–120 days), T5 (121–150 days), T6 (150–180 days), T7 (181–240 days), T8 (211–240 days), T9 (241–270 days), T10 (271–300 days), T11 (301–330 days) and T12 (331–360 days).
The study then examined the correlation of antibody titer with SARS-CoV-2 infection status (previously infected vs uninfected), vaccine type (Covishield vs Covaxin), age (18–44, 45–59, and > 60 years), gender (male or female), and the presence of comorbidities (present or absent). The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines [13].
Statistical Analysis
The normality of the data was assessed by Kolmogorov–Smirnov Z test. The continuous variables were expressed as medians and interquartile ranges, and categorical variables were expressed as frequencies and percentages. The differences between the categorical variables were analyzed by chi-square or Fisher’s exact test and the continuous variables by unpaired t-test or Mann–Whitney test. After logarithmic transformations of antibody titers, the study calculated the geometric mean titers (GMT) and 95% confidence interval (CI). For data presented as GMT, the study used parametric tests and independent sample t-tests to compare antibody titers for the entire cohort with its correlates. Statistical analysis was carried out with Statistical Package for Social Sciences (SPSS Complex Samples) Software Version 16.0 for windows, SPSS Inc., Chicago, IL, USA, with Microsoft Word and Excel used to generate graphs and tables.
Result
A total of 2069 participants were included in the study who had taken both the doses of COVID-19 vaccination and had submitted 2330 samples. The study evaluated 1863 unique samples and serial samples from 206 participants. The median age of the participants was 38 years (range 18–87 years), and 55.3% (1145/2069) of participants were male.
Following both the doses of the vaccine at various time intervals, the entire cohort's seropositivity along with GMT (95% CI) is shown in Table 1 and Fig. 1a. Geometric mean titers (GMT) decreased from the previous month by 17.2% at T4 and 25.7% at T7. However, GMT displayed a rising trend from T9 till T12.
Table 1.
Temporal pattern of COVID-19 antibody of the cohort
| Days since second dose of COVID-19 vaccine | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T0 | T1 | T2 | T3 | T4 | T5 | T6 | T7 | T8 | T9 | T10 | T11 | T12 | |
| N | 231 | 464 | 620 | 308 | 174 | 108 | 54 | 57 | 50 | 67 | 106 | 71 | 20 |
| SP (N) | 205 | 414 | 568 | 283 | 146 | 101 | 51 | 48 | 45 | 59 | 99 | 65 | 20 |
| SP (%) | 88.7 | 89.2 | 91.6 | 91.9 | 83.9 | 93.5 | 94.4 | 84.2 | 90.0 | 88.1 | 93.4 | 91.5 | 100 |
| GMT | 4.7 | 5.6 | 5.8 | 5.8 | 4.8 | 6.6 | 7.4 | 5.5 | 5.3 | 6.0 | 6.1 | 7.1 | 9.0 |
| 95% CI | 4.0–5.4 | 5.1–6.2 | 5.3–6.3 | 5.2–6.5 | 4.0–5.8 | 5.6–7.8 | 6.0–9.1 | 4.1–7.4 | 3.9–7.2 | 4.7–7.7 | 5.1–7.3 | 5.8–8.6 | 7.3–11.2 |
N: No: of participants; GMT: Geometric mean titers (Index); CI: 95% confidence interval; SP: Seropositivity
T0: < 14 days; T1: 14–30 days; T2: 31–60 days; T3:61–90 days; T4: 91–120 days; T5:121–150 days; T6: 151–180 days; T7:211–240 days; T8:211–240 days; T9:241–270 days; T10:271 – 300 days; T11:301–330 days; T12:331–360 days
Fig. 1.
Trend of COVID-19 antibody of (a) entire cohort; b in respect to type of immunity (Hybrid immunity/Naïve immunity; c in respect to type of vaccine (Covaxin/Covishield); d in respect to gender (Male/Female); e in respect to presence of comorbidities (present/absent); f in respect to age (18–44 /45–59/ > 60 yrs.)
Correlation of SARS-CoV-2 Antibody Status After Receiving Both Doses of the Vaccine with Previous SARS-CoV-2 Infection.
A total of 430 (20.8%) participants had a documented SARS-CoV-2 infection. Participants with previous SARS-CoV-2 infection with hybrid immunity (immunity from both vaccination and infection) had higher GMT in all time points than participants with vaccine-induced immunity (naive immunity). The trend of antibody titer in both groups showed a gradual decline at T4, but only in participants with naive immunity did exhibit a significant decline at T7. However, for those with hybrid immunity, the antibody titer remained relatively constant from T5. Table 2 and Fig. 1b.
Table 2.
Temporal pattern of COVID-19 antibody of the cohort with relation to the history of previous COVID infection and vaccine type
| Days since second dose of vaccine | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T0 | T1 | T2 | T3 | T4 | T5 | T6 | T7 | T8 | T9 | T10 | T11 | T12 | ||
| Immunity | Comparing participants' SARS-CoV-2 antibody titer after receiving both doses of the vaccine with prior SARS-CoV-2 infection and vaccine-induced (naive immunity) | |||||||||||||
| Naive | N | 175 | 380 | 483 | 243 | 129 | 79 | 43 | 41 | 45 | 59 | 90 | 64 | 16 |
| Immunity | SP (N) | 152 | 330 | 433 | 220 | 102 | 72 | 40 | 32 | 40 | 51 | 83 | 58 | 16 |
| (1847) | SP (%) | 86.9 | 86.8 | 89.6 | 90.5 | 79.1 | 91.1 | 93 | 78 | 88.9 | 86.4 | 92.2 | 92.1 | 100 |
| GMT | 4.1 | 5.0 | 5.1 | 5.2 | 4.0 | 5.8 | 6.8 | 4.5 | 4.9 | 5.6 | 5.6 | 6.1 | 8.8 | |
| 95% CI | 3.4–4.9 | 4.4–5.6 | 4.7–5.7 | 4.5–5.9 | 3.2–5.1 | 4.6–7.2 | 5.2–8.9 | 3.0–6.6 | 3.5–6.9 | 4.3–5.6 | 4.5–6.9 | 5.7–8.7 | 6.7–9.6 | |
| Hybrid | N | 56 | 84 | 137 | 65 | 45 | 29 | 11 | 16 | 5 | 8 | 16 | 8 | 4 |
| Immunity | SP (N) | 53 | 84 | 135 | 63 | 44 | 29 | 11 | 16 | 5 | 8 | 16 | 7 | 4 |
| (483) | SP (%) | 94.6 | 100 | 98.5 | 96.9 | 97.8 | 100 | 100 | 100 | 100 | 100 | 100 | 87.5 | 100 |
| GMT | 7.3 | 9.7 | 8.8 | 8.8 | 8.2 | 9.6 | 10 | 9.6 | 10 | 10 | 10 | 9.1 | 10 | |
| 95% CI | 5.9–9.0 | 9.4–10 | 8.0–9.6 | 7.6–10 | 6.9–9.9 | 9.0–10 | 10–10 | 8.9–10 | 10–10 | 10–10 | 10–10 | 3.1–16.4 | 10–10 | |
| p value | < 0.001 | < 0.001 | < 0.001 | < 0.001 | 0.001 | 0.002 | 0.096 | 0.006 | 0.113 | 0.08 | 0.01 | 0.923 | 0.63 | |
| Vaccine | Comparing participants' SARS-CoV-2 antibody titer after receiving both doses of the vaccine with type of vaccines (Covaxin and Covishield) | |||||||||||||
| Covaxin | N | 193 | 406 | 533 | 269 | 135 | 96 | 41 | 44 | 42 | 58 | 98 | 70 | 20 |
| (2005) | SP (N) | 169 | 357 | 481 | 244 | 107 | 89 | 38 | 35 | 37 | 50 | 91 | 64 | 20 |
| SP (%) | 87.6 | 87.9 | 90.2 | 90.7 | 79.3 | 92.7 | 92.7 | 79.6 | 88.1 | 86.2 | 92.9 | 91.4 | 100 | |
| GMT | 4.2 | 5.2 | 5.4 | 5.4 | 4.0 | 6.3 | 6.7 | 4.9 | 4.9 | 5.7 | 5.9 | 7.0 | 9.0 | |
| 95% CI | 3.6–5.0 | 4.7–5.8 | 4.9–5.9 | 4.8–6.1 | 3.2–5 | 5.2–7.6 | 5.1–8.8 | 3.4–7.1 | 3.4–6.9 | 4.3–7.5 | 4.9–7.2 | 7.0–8.6 | 9.1–12.6 | |
| Covishield | N | 38 | 58 | 87 | 39 | 39 | 12 | 13 | 13 | 8 | 9 | 8 | 1 | 0 |
| (325) | SP (N) | 36 | 57 | 87 | 39 | 39 | 12 | 13 | 13 | 8 | 9 | 8 | 1 | 0 |
| SP (%) | 94.7 | 98.3 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 0 | |
| GMT | 7.8 | 9.3 | 9.4 | 9.1 | 9.4 | 10 | 10 | 8.4 | 8.3 | 8.3 | 8.5 | 10 | 0 | |
| 95% CI | 5.9–10.3 | 8.3–10.4 | 8.9–10 | 8.1–10.1 | 8.7–10 | 10–10 | 10–10 | 7.1–10.0 | 6.2–11.1 | 6.1–11.3 | 5.9–12.3 | 10–10 | 0–0 | |
| p value | < 0.001 | < 0.001 | < 0.001 | < 0.001 | < 0.001 | 0.09 | 0.11 | 0.12 | 0.20 | 0.30 | 0.30 | 0.68 | < 0.001 | |
N: No: of participants; GMT: Geometric mean titers (Index); CI: 95% confidence interval; SP: Seropositivity
T0: < 14 days; T1: 14–30 days; T2: 31–60 days; T3:61–90 days; T4: 91–120 days; T5:121–150 days; T6: 151–180 days; T7:211–240 days; T8:211–240 days; T9:241–270 days; T10:271 – 300 days; T11:301–330 days; T12:331–360 days
Correlation of SARS-CoV-2 Antibody Status After Receiving Both Doses of the Vaccine with the Type of Vaccine
The majority of participants (1767;85.4%) had been vaccinated by Covaxin (BBV152) and the rest (302;14.6%) by Covishield (ChAdOx1 nCoV-19). The median days between the two doses of the vaccine was 32 days (IQR: 30–36 days) for Covaxin and 59 days (IQR: 33–93 days) for Covishield. The median age of participants in the Covaxin vaccine group was 38 yrs. (31–48 yrs.) and 39 yrs. (30–52 yrs.) for Covishield vaccine. Male to female ratio was 1.2:1 (male: 972; female:795) for Covaxin and 1.3:1 (male:173; female:129) for Covishield vaccine. In participants with a history of SARS-CoV-2 infection, 20.1% (355/1767) and 24.8% (75/302) had received the Covaxin and Covishield vaccines, respectively. The GMT of anti-RBD SARS-CoV-2 antibodies for Covishield vaccine participants were higher than those who had taken the Covaxin vaccine group at all time points.
The antibody titers for participants who received the Covishield vaccine showed an upward trend with a slight dip in T3, then a raise at T4 until T6 and then a significant dip from T7, remaining constant until T10, a slight upward trend at T11 and no patients at T12. On the other hand, participants who received the Covaxin vaccine exhibited a similar trend as the Covishield up until T3, but then suddenly dipped at T4, rose at T5 until T6, and then exhibited a similar trend to Covishield as a significant downward trend from T7, but then an upward trend from T9 until T12. Table 2 and Fig. 1c.
Correlation of SARS-CoV-2 Antibody Status After Receiving Both Doses of the Vaccine with the Gender
The majority of the participants were male (55.3%;1145/2069). However, there were no apparent gender disparities in the antibody titers across all time points, and the trend was the same for both male and female participants. Table 3 and Fig. 1d.
Table 3.
Temporal pattern of COVID-19 antibody of the cohort with relation to the gender and presence of comorbidities
| Days since second dose of vaccine | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Gender | T0 | T1 | T2 | T3 | T4 | T5 | T6 | T7 | T8 | T9 | T10 | T11 | T12 | |
| Comparing participants' SARS-CoV-2 antibody titer after receiving both doses of the vaccine with gender (Male and Female) | ||||||||||||||
| Male | N | 125 | 255 | 321 | 169 | 87 | 65 | 37 | 27 | 30 | 43 | 77 | 55 | 16 |
| (1307) | SP (N) | 114 | 230 | 295 | 163 | 72 | 61 | 35 | 21 | 28 | 37 | 71 | 51 | 16 |
| SP (%) | 91.2 | 90.2 | 91.9 | 96.4 | 82.8 | 93.8 | 94.6 | 77.8 | 93.3 | 86.0 | 92.2 | 92.7 | 100 | |
| GMT | 5.3 | 5.7 | 5.9 | 6.4 | 5.0 | 6.8 | 7.3 | 4.7 | 5.9 | 5.8 | 5.8 | 7.6 | 8.8 | |
| 95% CI | 4.4–6.4 | 5.0–6.6 | 5.3–6.5 | 5.6–7.2 | 3.9–6.6 | 5.5–8.5 | 5.7–9.4 | 2.8–7.9 | 4.2–8.5 | 4.3–8.0 | 4.6–7.4 | 6.2–9.3 | 6.7–11.6 | |
| Female | N | 106 | 209 | 299 | 139 | 87 | 43 | 17 | 30 | 20 | 24 | 29 | 16 | 4 |
| (1023) | SP (N) | 91 | 184 | 273 | 120 | 74 | 40 | 16 | 27 | 17 | 22 | 28 | 14 | 4 |
| SP (%) | 85.8 | 88.0 | 91.3 | 86.3 | 85.1 | 93.0 | 94.1 | 90.0 | 85.0 | 91.7 | 96.6 | 87.5 | 100 | |
| GMT | 4.0 | 5.5 | 5.7 | 5.1 | 4.6 | 6.3 | 7.4 | 6.4 | 4.4 | 6.3 | 6.8 | 5.5 | 10.0 | |
| 95% CI | 3.1–5.2 | 4.8–6.4 | 5.0–6.4 | 4.2–6.2 | 3.6–6.0 | 4.8–8.3 | 4.8–11.6 | 4.7–8.8 | 2.5–7.9 | 4.1–9.5 | 5.0–9.1 | 5.5–9.8 | 10–10 | |
| p value | 0.07 | 0.72 | 0.67 | 0.06 | 0.66 | 0.68 | 0.96 | 0.30 | 0.35 | 0.78 | 0.48 | 0.18 | 0.63 | |
| Comparing participants' SARS-CoV-2 antibody titer after receiving both doses of the vaccine with comorbidities (present or absent) | ||||||||||||||
| Absent | N | 182 | 372 | 480 | 260 | 144 | 81 | 46 | 43 | 39 | 55 | 93 | 63 | 19 |
| (1877) | SP (N) | 162 | 330 | 443 | 237 | 119 | 76 | 44 | 36 | 35 | 48 | 88 | 58 | 19 |
| SP (%) | 89.0 | 88.7 | 92.3 | 91.2 | 82.6 | 93.8 | 95.7 | 83.7 | 89.7 | 87.3 | 94.6 | 92.1 | 100 | |
| GMT | 4.7 | 5.6 | 6.0 | 5.7 | 4.8 | 6.5 | 7.7 | 5.9 | 5.1 | 6.1 | 6.3 | 7.3 | 10.0 | |
| 95% CI | 3.9–5.5 | 5.0–6.2 | 5.5–6.6 | 5.0–6.4 | 3.9–5.9 | 5.4–7.9 | 6.3–9.6 | 4.3–8.0 | 3.6–7.2 | 4.7–8.1 | 5.2–7.6 | 5.9–8.9 | 10–10 | |
| Present | N | 49 | 92 | 140 | 48 | 30 | 27 | 8 | 14 | 11 | 12 | 13 | 8 | 1 |
| (453) | SP (N) | 43 | 84 | 125 | 46 | 27 | 25 | 7 | 12 | 10 | 11 | 11 | 7 | 1 |
| SP (%) | 87.8 | 91.3 | 89.3 | 95.8 | 90.0 | 92.6 | 87.5 | 85.7 | 90.9 | 91.7 | 84.6 | 87.5 | 100 | |
| GMT | 4.8 | 5.8 | 5.0 | 6.4 | 5.2 | 6.9 | 5.6 | 4.6 | 5.9 | 5.4 | 4.8 | 5.6 | 1.3 | |
| 95% CI | 3.5–6.5 | 4.7–7.2 | 4.2–6.1 | 5.0–8.0 | 3.5–7.8 | 4.8–10 | 2.2–13.9 | 2.1–10.0 | 2.8–12.3 | 2.8–10.1 | 2.4–9.5 | 2.2–13.9 | 1.3–1.3 | |
| p value | 1.00 | 0.95 | 0.03 | 0.74 | 0.88 | 0.48 | 0.34 | 0.42 | 0.57 | 0.38 | 0.36 | 0.43 | 1.00 | |
N: No: of participants; GMT: Geometric mean titers (Index); CI: 95% confidence interval; SP: Seropositivity
T0: < 14 days; T1: 14–30 days; T2: 31–60 days; T3:61–90 days; T4: 91–120 days; T5:121–150 days; T6: 151–180 days; T7:211–240 days; T8:211–240 days; T9:241–270 days; T10:271–300 days; T11:301–330 days; T12:331–360 days
Correlation of SARS-CoV-2 Antibody Status After Receiving Both Doses of the Vaccine with the Presence of Comorbidities
Only 19.7% (408/2069) of participants were suffering from comorbidities. The majority of participants (164;40.2%) had hypertension, which was followed by diabetes mellitus (145;35.5%), thyroid disorders (96;23.5%), asthma (59;14.5%), cardiovascular disorders (30;7.4%), renal diseases (9;2.2%), malignancies (9;2.2%), connective tissue disorders (6;1.5%), liver diseases (7;1.7%), COPD (3;0.7%) and obesity (2;0.5%).
The antibody titers in both groups of participants with and without comorbidities were analyzed. The results showed that both groups exhibited a decline in antibodies from T5 to T7, but from T8, the group without comorbidities showed a non-significant rising pattern while the group with comorbidities showed a non-significant declining trend. Table 3 and Fig. 1e.
Correlation of SARS-CoV-2 Antibody Status After Receiving Both Doses of the Vaccine with Age
Majority of the participants [1331;64.3%] were in the 18–44 yrs., followed by 45–59 yrs. [593;28.7%] and ≥ 60 yrs. [145;7%]. In all age groups, antibody titers increased in the first three months (T0–T3), then declines in T4, with fluctuating trends in the following months. At T7, there was a significant dip in the level of antibodies. At T12, the 18–44 years and 45–59 years age group participants showed a rising trend in the level of antibodies, while the participants aged 60 years or above displayed a declining trend. This is demonstrated in Table 4 and Fig. 1f.
Table 4.
Temporal pattern of COVID-19 antibody of the cohort with relation to the age (18–44, 45–59, ≥ 60 yrs.)
| Days since second dose of vaccine | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age | T0 | T1 | T2 | T3 | T4 | T5 | T6 | T7 | T8 | T9 | T10 | T11 | T12 | |
| Comparing participants' SARS-CoV-2 antibody titer after receiving both doses of the vaccine with gender (Male and Female) | ||||||||||||||
| 18–44 yrs | N | 146 | 302 | 388 | 209 | 117 | 66 | 38 | 31 | 32 | 46 | 60 | 48 | 10 |
| (1493) | SP (N) | 131 | 267 | 356 | 192 | 94 | 62 | 36 | 28 | 28 | 39 | 57 | 44 | 10 |
| SP (%) | 89.7 | 88.4 | 91.8 | 91.9 | 80.3 | 93.9 | 94.7 | 90.3 | 87.5 | 84.8 | 95.0 | 91.7 | 100 | |
| GMT | 4.8 | 5.5 | 6.0 | 6.1 | 4.4 | 6.5 | 7.3 | 7.0 | 4.3 | 5.5 | 5.9 | 7.5 | 10.0 | |
| 95% CI | 4.0–5.8 | 4.8–6.3 | 5.5–6.6 | 5.3–6.9 | 3.5–5.6 | 5.2–8.1 | 5.7–9.5 | 5.1–9.5 | 2.8–6.6 | 4.0–7.7 | 4.6–7.6 | 5.9–9.3 | 10–10 | |
| 45–59 yrs | N | 74 | 135 | 197 | 85 | 41 | 32 | 12 | 18 | 12 | 15 | 29 | 18 | 9 |
| (677) | SP (N) | 65 | 123 | 179 | 77 | 38 | 30 | 11 | 16 | 12 | 14 | 28 | 16 | 9 |
| SP (%) | 87.8 | 91.1 | 90.9 | 90.6 | 92.7 | 93.8 | 91.7 | 88.9 | 100 | 93.3 | 96.6 | 88.9 | 100 | |
| GMT | 4.5 | 6.0 | 5.2 | 5.1 | 6.0 | 6.9 | 6.8 | 6.2 | 9.2 | 6.2 | 7.5 | 6.0 | 10.0 | |
| 95% CI | 3.5–5.9 | 5.1–7.0 | 4.5–6.1 | 4.0–6.5 | 4.3–8.4 | 5.2–9.1 | 3.8–12.2 | 3.9–9.8 | 7.7–11.0 | 3.9–9.8 | 5.6–9.9 | 3.6–10.0 | 10–10 | |
| ≥ 60 yrs | N | 11 | 27 | 35 | 14 | 16 | 10 | 4 | 8 | 6 | 6 | 17 | 5 | 1 |
| (160) | SP (N) | 9 | 24 | 33 | 14 | 14 | 9 | 4 | 4 | 5 | 6 | 14 | 5 | 1 |
| SP (%) | 81.8 | 88.9 | 94.3 | 100 | 87.5 | 90.0 | 100 | 50.0 | 83.3 | 100.0 | 82.4 | 100 | 100 | |
| GMT | 3.9 | 5.2 | 6.6 | 5.7 | 5.5 | 6.7 | 10.0 | 1.7 | 5.1 | 10.0 | 4.8 | 7.5 | 1.3 | |
| 95% CI | 1.5–10.1 | 3.1–8.7 | 4.8–9.2 | 3.5–9.4 | 3.0–10.0 | 3.1–14.8 | 10–10 | 1.7–0.4 | 1.5–17.0 | 10–10 | 2.6–8.6 | 3.3–16.9 | 1.3–1.3 | |
| p value | 0.90 | 0.99 | 0.12 | 0.48 | 0.48 | 0.87 | 0.65 | 0.01 | 0.10 | 0.33 | 0.27 | 0.66 | 1.00 | |
N: No: of participants; GMT: Geometric mean titers (Index); CI: 95% confidence interval; SP: Seropositivity
T0: < 14 days; T1: 14–30 days; T2: 31-–0 days; T3:61–90 days; T4: 91–120 days; T5:121–150 days; T6: 151–180 days; T7:211–240 days; T8:211–240 days; T9:241–270 days; T10:271–300 days; T11:301–330 days; T12:331–360 days
Discussion
The World Health Organisation (WHO) declared SARS-CoV-2, the virus that caused COVID-19, to be a pandemic on March 11, 2020. The virus had a significant impact on global health and the socioeconomic system [14]. Even after successive waves of varying intensity and severity, COVID-19 cases continued to follow a waxing and waning pattern predominantly due to its contagiousness and various emergent strains. The most effective preventive strategy proven till date against SARS-CoV-2 was vaccination. This helped determine the duration and magnitude of immunity attained by SARS-CoV-2 infection or vaccine, which characterized the risk of reinfection and the need for a booster dose [15].
In SARS-CoV-2, three different seroconversion patterns were reported. In some cases, IgM emerges before IgG as expected, whereas in other cases, IgG appears before IgM, and occasionally both existed at the same time [16, 17]. Few studies reported a waning of humoral immune responses to vaccines by 3 to 6 months [12, 18]. Singh Ak et al., reported a 44% decline in GMT at 6 months compared to the peak titer period i.e., 21 days after the second dose for both Covishield and Covaxin vaccine [18]. Choudhary HR et al., also reported a twofold decline in antibody titers among Covishield after 4 months and a fourfold decline in antibody titers among Covaxin after 2 months [12]. Such progressive decline is also noted with other COVID vaccines as reported by Campo et al., they concluded that a 59.6% decline is seen in naive individuals and a 67.8% decline in individuals with the previous infection at day 140 after a two-dose regimen of BNT162b2 vaccine [19]. Naaber P et al., also found a decline in antibody levels at 3 month and at 6-month post-vaccination as well as the antibodies efficiently blocked ACE2 receptor to binding to SARS-CoV-2 spike protein of five variants of concern at one week but decreases at three months [20]. This study also concluded that there was a dip in anti-RBD SARS-CoV-2 total antibodies titers at T4 (91–120 days) and T7 (181–240 days) but was robust for at least a year after the second dose of either vaccine. The mechanisms underlying this decline in antibody levels are not fully understood, but may involve a loss of short-lived plasma cells, depletion of lymphocytes involved in immune signaling, damage to germinal centers of lymph nodes, or defective BCL6 + follicular T-cells that are unable to activate memory B cells. [14].
The anti-RBD SARS-CoV-2 total antibody titers were significantly higher in those with hybrid immunity compared to vaccine-induced immunity in the study. Ali H et al., also reported a decline in IgG (SERION; ELISA) and neutralizing antibodies in vaccinated individuals [BBV-152 and AZD1222] without previous infection compared to individuals with hybrid immunity [16]. According to a study by Kumar NP et al., a single dose of the BBV-152 vaccine develops humoral immunity in previously infected individuals to the same extent that a two-dosage regimen does in previously unvaccinated people [21]. Suggesting a natural infection enhances the immunity offered by vaccination, as it is equivalent to another dose of vaccine. Therefore, a history of past infection should be considered when recommending booster doses.
In the study, seropositivity for anti-RBD SARS-CoV-2 was significantly higher in Covishield recipients, compared to Covaxin. Few studies reported similar findings [12, 18]. This could be due to either differential immunogenic response due to the difference in spike antigen dose in each vaccine (vector-based vs. inactivated whole virion) or due to a longer interval between the first and second dose for Covishield.
Notably, no difference in seropositivity rate was observed amongst both genders. However, the titer of anti-spike antibodies is declining by 8 months for age ≥ 60 years, and people with comorbidities. Singh Ak et al., reported a similar finding concluding that at age ≥ 60 years, male, people with any comorbidities particularly hypertensive had less anti-spike antibody GMT [18]. Naaber P et al., also found a negative correlation between antibody response and the age of vaccinated individuals [20]. However, a few studies also reported no difference in antibody titer concerning age, gender and comorbidities [6, 22]. The findings suggested that as humoral immunity declines with age, individuals that are elderly or who have comorbid diseases should periodically receive booster doses.
To the best of the study’s knowledge, this would be the first of its kind to have investigated trends in anti-SARS-CoV-2 antibodies for a year after the administration of both vaccine doses. The present study's limitation, however, due to the unavailability of diluent, they were also unable to determine the dilution value for samples with higher linearity values, considering that several patients had undiluted plateaued results, this may have underestimated the GMT in Covishield recipients when compared to Covaxin recipients. Furthermore, they were unable to evaluate neutralizing antibodies, cell immune response, or cytokines. Future research was required to determine whether the observed variation in antibody level corresponds to a variation in the duration of protection, the protection against variants of concern, and the risk of transmission.
The study concluded that post-vaccination testing of multiple antibody levels was an essential and feasible method for following vaccinated individual’s monitoring and could help identify those who required additional boosting due to low responsiveness, may need a third dose of the vaccine sooner, or may not require a second dose due to prior SARS-CoV-2 infection [23].
Ethical Approval
The approval of the Institutional Ethical Committee (AIIMS, New Delhi) was obtained before initiating the study (IEC-181/05.03.2021, RP-10/2021).
Informed Consent
Informed consent was taken from the participants.
Funding
None.
Declarations
Conflict of interest
The author declares that they have no conflict of interest.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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