Skip to content
Publicly Available Published by De Gruyter April 26, 2023

Safety, immunogenecity and effectiveness of ChAdOx1 nCoV-19 vaccine during the second wave of pandemic in India: a real-world study

  • Preeti Chavan , Rajashree Dey , Renita Castelino , Akshay Kamble , Pratik Poladia , Rajani Bagal , Monica Jadhav , Aditi Shirsat , Ashish Chavan , Sachin Dhumal , Sharath Kumar , Manjunath Nookala Krishnamurty , Vivek Bhat , Atanu Bhattacharjee and Vikram Gota EMAIL logo

Abstract

Objectives

This real-world study was conducted to assess the adverse effects following immunization (AEFI) and immunogenicity of ChAdO×1 nCoV-19 vaccine in terms of neutralising antibody titers and to study the effects of covariates such as age, sex, comorbidities and prior COVID status on these outcomes. Also, the effectiveness of the vaccine based on interval between the two doses was also investigated.

Methods

A total of 512 participants (M/F=274/238) aged 35(18–87) years comprising a mixed population of healthcare workers, other frontline workers and general public were enrolled between March and May 2021. Records for adverse events if any were collected telephonically by following up with participants up to 6 months post first dose and graded as per Common Terminology Criteria for Adverse Events (CTCAE) version 5. Blood samples for measuring antibody titers against the receptor binding domain (RBD) were collected serially using a convenient sampling strategy up to 6 months after the first dose. Data on breakthrough COVID infection was collected telephonically till December 2021.

Results

Incidence of local reactions was higher after first dose at 33.4 % (171/512) compared to those after second dose at 12.9 % (66/512). Commonest side effect observed was injection site pain after the first (87.1 %; 149/171) and second (87.9 %; 56/66) dose respectively. Among systemic reactions, fever was the most common manifestation followed by myalgia and headache. Female sex (p<0⸱001) and age less than 60 years (p<0⸱001) had significantly higher predilection for systemic toxicities. Age ≤60 years (p=0.024) and prior-COVID (p<0.001) were found to be significantly associated with higher antibody titers, however, no association was found between these variables and breakthrough COVID infection. Longer spacing between the doses (≥6 weeks) was found to offer better protection against breakthrough infection compared to a spacing of 4 weeks. All breakthroughs were mild-moderate in severity, not requiring hospitalization.

Conclusions

The ChAdOx1 nCov-19 vaccine is apparently safe and effective against SARS-CoV-2 virus infection. Prior COVID infection and younger age group achieve higher antibody titers, but no additional protection. Delaying the second dose up to at least 6 weeks is more effective compared to shorter spacing between doses.

Introduction

The University of Oxford in collaboration with Vaccitech co-invented and developed ChAdOx1 nCoV-19 vaccine using the full length structural genetic material of the SARS-CoV-2 virus spike protein [1, 2]. Post-vaccination, this surface spike protein is reproduced and primes the immune system to neutralize the SARS-CoV-2 virus whenever it is contracted by the body [3]. The anti-spike protein antibodies can defend against viral infection by blocking the entry of the virus into the host cells. In India this vaccine is available as Covishield.

The evaluation of safety of vaccines is indispensable during their development. Safety data is collected both actively and passively through the spontaneous reports of suspected adverse events following immunization (AEFI) that are submitted by physicians and vaccinees [4, 5]. No serious adverse effects were observed during the phase 1/2 and 2/3 clinical trials of ChAdOx1 nCoV-19 [1, 6, 7]. It was also observed that the second and third doses of the vaccine were less reactogenic compared to the first dose [2]. Less commonly thrombotic adverse events (28 in 17 million recipients) were observed in post-marketing studies [5].

In addition to being safe a vaccine has to provide protection against the pathogen of interest. The immunogenicity of a vaccine is its ability to evoke an immune response in an individual and can be assessed by the measurement of neutralizing antibodies (nAb) present in blood following vaccination. The presence of neutralizing antibody has been observed in the blood samples of recipients with a single dose of vaccine up to one year [2]. In fact, the vaccine elicited neutralizing antibodies in 91 % of recipients following the first dose and in almost all vaccinees following the second dose [1, 7].

These findings, however, were in a trial setting. Monitoring the outcomes of vaccination in a real-world scenario having greater diversity in demographics is important. The aim of this study was to assess the adverse effects following immunization (AEFI) and immunogenicity of ChAdOx1 nCoV-19 vaccine in terms of neutralising antibody titers, in a real-world setting, and to study the effects of covariates such as age, sex, comorbidities and prior COVID status on these outcomes. Also, the effectiveness of the vaccine based on interval between the two doses was also investigated.

Materials and methods

A mixed population of healthcare workers, other frontline workers and general public were enrolled in this study after due consent between March and May 2021. The participants received their first dose of vaccination between 16th January and 21st May 2021. All participants received their vaccine shots in our institute’s vaccination centre run by the local municipal corporation. Healthcare workers and other frontline workers of our hospital were contacted and enrolled on campus whereas the general public were contacted and enrolled from the vaccination centre. The baseline demographic information of all participants was collected. In accordance with the changing policies of the government, the interval between two doses of the vaccine varied from 4 weeks, 6–8 weeks to 12–14 weeks at different points in time during the study.

Adverse events

Records for adverse events if any were collected telephonically by following up with participants up to 6 months (days 7, 14, 28, 35, 42, 56, 90, 120,180) post first dose. The adverse events were recorded as local and systemic reactions. Common Terminology Criteria for Adverse Events (CTCAE) version 5 was used to grade the adverse events [8].

Blood sample collection and processing

The blood samples of the participants were collected serially at any or all of the following timepoints viz., days 7, 14, 28, 35, 42, 56, 90, 120,180 after the first dose using convenient sampling strategy. Serum samples of study participants were analysed for antibody (Ab) titer using a 1-step antigen sandwich immunoassay (COV2T; Siemens Healthcare Diagnostic Inc, NY, USA) on Atellica fully automated immunoassay analyser. The Atellica IM COV2T assay is a fully automated 1-step antigen sandwich immunoassay using acridinium ester chemiluminescent technology, in which antigens are bridged by antibodies present in the sample. The Solid Phase contains a preformed complex of streptavidin-coated microparticles, and biotinylated SARS-CoV-2 spike 1 receptor binding domain (S1 RBD) recombinant antigens. This reagent is used to capture anti-SARS-CoV-2 antibodies in the sample. The Lite Reagent contains acridinium-ester-labelled SARS-CoV-2 recombinant S1 RBD antigens used to detect anti-SARS-CoV-2 antibodies bound to the Solid Phase. A direct relationship exists between the amount of SARS-CoV-2 antibodies pre results are reported in Index Units with <1.0 Index reported as nonreactive, ≥1.0 Index as reactive for the presence of antibodies. The linearity of the assay is 0⸱60–75⸱00 Index. Samples with value more than 75 were further diluted with Atellica IM Multi-Diluent 2 and results were calculated with appropriate dilution factors.

Breakthrough COVID infection

The participants were actively followed up for a median of 10 (7–11) months after the first dose to gather information on breakthrough COVID infection. Breakthrough infection was defined as RT-PCR positive for SARS-CoV-2 at least 14 days after the second dose of the vaccine [9, 10]. The severity of the infection, hospitalization if any, and the duration, requirement of oxygen and final outcome were documented for each breakthrough.

Ethical approval

The study was approved by the Ethics Committee of TMC-ACTREC, India (approval number: 900789). All trial participants provided written informed consent prior to their enrolment. The study was carried out in accordance with the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration.

Statistical analysis

Wherever required, participants were categorized into three groups based on the interval between two vaccine doses: Group 1 (4 weeks), Group 2 (6–8 weeks) and Group 3 (12–16 weeks). Baseline characteristics such as sex, age (<60 years and ≥60 years), BMI (≤18.5, 18.5–25.0, ≥25.0), presence or absence of comorbidities, and presence or absence of prior COVID-19 infection and their association with adverse events were evaluated using the Chi-squared test. Ab titers were measured on nine timepoints across 180 days using sparse sampling strategy. Individuals who had at least one titer value were included in this analysis. The mean Ab titers were compared on different days and between the groups by linear mixed effect modelling. The effect of baseline covariates such as age, BMI, sex, comorbidities and prior-COVID were explored on repeatedly measured titer values of these individuals. It was anticipated that the baseline characteristics would have some impact on an individual’s titer value, and therefore, the effect was explored by linear mixed effect modelling. The linear mixed-effect models were prepared with univariate context. Variables that emerged significant in univariate analysis were included in the multivariable analysis to assess their effect on Ab titers. The level of significance was considered as 5 % for all univariate and multivariable analyses. Both types of analysis were performed using open-source software R with “lme4” and “lmertest” packages.

Time to breakthrough infection was plotted using Kaplan-Meier method and compared between groups using the log-rank test. Hazard ratios were calculated by Cox proportional hazard assumption. Vaccine recipients who turned COVID positive within 14 days of the second dose were excluded from this analysis and so were patients who had history of COVID prior to vaccination. Different types of adverse events and their incidence after first and second dose of vaccine were analysed descriptively. Systematic and local reactions were analysed separately and presented. The role of baseline characteristics on the incidence of adverse events was explored using Chi-squared test for association.

Results

A total of 512 participants comprising of 274 males and 238 females with a median (range) age of 35(18–87) years were enrolled in the study. The baseline characteristics of the participants is shown in Table 1. Of note, 60 participants (11.17 %) had had previous COVID infection as diagnosed by a positive RT-PCR test, at least four (range: 4–38) weeks prior to first dose of vaccination, and 10 participants had SARS-CoV-2 infection between the first dose and day 14 of second dose.

Table 1:

Baseline characteristics of study participants (n=512).

Characteristic Sample size, n Percentage, %
Age, years
 <60 468 91.41
 ≥60 44 08.59
Sex
 Female 274 53.52
 Male 238 46.48
BMI, %
 <18.5 27 05.27
 18.5≤BMI<24.9 265 51.76
 ≥25 220 42.97
Comorbidities 122 23.83
 Hypertension 55 10.74
 Diabetes mellitus 46 9
 Bronchial asthma 7 1.37
 Dyslipidemia 4 0.8
 Hypothyroidism 20 3.9
 Others 25 4.88
History of allergies 13 2.53
Previous COVID infection 60 11.17
  1. BMI, body mass index.

Adverse events

A total of 171 local reactions were observed in 512 volunteers after the first dose of the vaccine, while the incidence was far less following the second dose (66 reactions in 512 individuals). Injection site pain was the most common side effect, accounting for 87.1 % (149/171) and 87.9 % (56/66) of all local reactions after the first and second dose respectively. The incidence of injection site pain was 29 % (149/512) after the first dose and 11 % (58/512) after the second dose. The local reactions were predominantly mild in nature, with only 17 % (29/171) and 7.6 % (5/66) of reactions being of grade ≥2 severity after the first and second dose respectively (Table 2A).

Table 2:

Frequency of local and systemic adverse events following vaccination (n=512).

A. Local
After dose n Mild (1) Moderate (2) Severe (3) Life-threatening (4)
Site pain 1 149 126 22 1 0
2 58 54 3 1 0
Site tenderness 1 11 9 2 0 0
2 3 2 1 0 0
Site swelling 1 9 5 4 0 0
2 4 4 0 0 0
Site erythema 1 2 2 0 0 0
2 1 1 0 0 0
Total local adverse events 1 171 142 28 1 0
2 66 61 4 1 0

B. Systemic

Fever 1 221 165 54 2 0
2 25 18 6 1 0
Headache 1 119 85 26 8 0
2 20 17 3 0 0
Myalgia 1 124 88 27 9 0
2 16 13 3 0 0
Fatigue 1 42 25 8 9 0
2 9 5 4 0 0
Malaise 1 15 11 4 0 0
2 3 2 1 0 0
Diarrhea 1 2 1 1 0 0
2 3 1 2 0 0
Nausea 1 13 9 4 0 0
2 6 4 2 0 0
Vomiting 1 4 4 0 0 0
2 0 0 0 0 0
Any other 1 82 67 11 4 0
2 15 11 4 0 0
Total systemic adverse events 1 622 455 135 32 0
2 97 71 25 1 0
  1. Graded as per CTCAE version 5.

The number of systemic side effects observed after the first and second dose of the vaccine is shown in Table 2B. Fever was the most common manifestation followed by myalgia and headache. Of the 622 events observed after the first dose, 455 (73.1 %) were of grade 1, 135 (21.7 %) of grade 2 and 32 (5.1 %) of grade 3 severity. Headache, myalgia, and fatigue were the commonly observed grade 3 toxicities, but the incidence of each of these events was less than 2 %. Grade 3 toxicities were almost invariably seen after the first dose with the exception of one case of grade 3 fever that occurred after the second dose. Brief hospitalisation was required for two participants after the first dose for high grade fever and for one participant after the second dose for syncopal attack. Female sex had significantly higher predilection for systemic toxicities compared to males (172/274 vs. 104/238; p<0.001). A similar predilection was also observed in volunteers aged less than 60 years compared to their older counterparts (265/468 vs. 11/44; p<0.001). No other covariate, including prior COVID diagnosis had any association with the occurrence of systemic toxicities (Table 3).

Table 3:

Association between demographic variables and systematic adverse events after the 1st dose of vaccination.

Variable Systematic reaction p-Value
Absent Present
Sex Male 134 104 0.000
Female 102 172
Age group <60 years 203 265 0.001
60 years 33 11
Comorbidities Absent 167 223 0.008
Present 69 53
Prior-COVID Absent 207 245 0.711
Present 29 31
BMI ≤18.5 12 15 0.225
18.5<BMI<25 113 152
≥25 111 109
  1. Association between the baseline demographic variables and systematic adverse events after 1st dose and the p-values are obtained by Chi-square test.

Antibody titers

The 512 participants received their vaccination in three distinct patterns based on the time interval between the first and the second dose. This included group 1 (4 weeks), group 2 (5–8 weeks) and group 3 (12–16) weeks. This was a result of changing policies of the government as regards to timing of the second dose. The baseline characteristics of the three groups of volunteers is shown in Supplementary Table 1. It is pertinent to mention here that the number of samples at all time-points within a group is not uniform since we employed a sparse sampling strategy, allowing flexibility to the participants to submit samples on the days of their choice or convenience. A total of 823 samples [median (range)=2(1–9)] were collected from the volunteers for the analysis of Ab titers. The mean and standard deviation (SD) of Ab titers by groups on different sampling days is shown in Table 4. All samples analysed on or after day 28, up to day 180, were found to be reactive. The mean Ab titers were compared on different days and between the groups by linear mixed effect modelling. No significant difference was observed between days (p=0.054) and groups (p=0.062).

Table 4:

Antibody titers following vaccination in groups based on interval between doses.

Group 1: 4 weeks interval (n=242) Group 2: 6–8 weeks interval (n=199) Group 3: 12–16 weeks interval (n=71)
Day of sample collection Sample size (n=379) Ab titer, index units Sample size (n=341) Ab titer, index units Sample size (n=103) Ab titer, index units
Mean Standard deviation Mean Standard deviation Mean Standard deviation
7 ± 1 7 159.21 305.26 31 186.79 323.34 9 181.54 221.82
14 ± 1 8 74.17 40.95 37 498.67 688.28 18 454.12 672.86
28 ± 2 9 218.73 333.1 35 462.56 493.98 17 391.1 448.54
35 ± 2 9 164.71 184.74 33 529.77 604.24 13 323.84 453.95
42 ± 2 32 291.41 375.32 33 370.99 494.91 14 272.81 311.45
56 ± 2 65 297.75 389.52 54 306.94 364.1 9 202.46 224.7
90 ± 7 149 282.02 416.23 73 258.75 311.22 14 266.8 350.2
120 ± 7 67 314.56 404.88 30 213.95 276.12 6 486.32 619.9
180 ± 7 33 146.8 93.95 15 153.74 66.48 3 172.1 72.94
  1. No significant difference observed between the three groups. Ab, antibodies.

Effect of demographic factors on antibody titers

The effect of variables such as age, sex, BMI, comorbidities (present/absent) and prior COVID (yes/no) on the antibody titers across days was evaluated using linear mixed effect model. Age less than 60 years and prior COVID were found to be significantly associated with higher antibody titers in the univariate analysis (Table 5). Multivariable analysis using a linear mixed effects model confirmed the covariate effects of age and prior COVID status on Ab titer values (R2=0.25) (Table 6). The median peak antibody titers were approximately 6 % higher in volunteers under 60 years of age compared to older volunteers (Figure 1A). Similarly, volunteers with history of COVID diagnosis prior to vaccination had 28 % higher median peak antibody titers compared to those who did not (Figure 1B). However, antibody titers on day 180 were not significantly different between the two age groups, although the effect of prior COVID on day 180 titers was statistically significant compared to those who had not contracted COVID before.

Table 5:

Summary table of univariate analysis.

Parameter Estimate SE t-Value p-Value
Model 1A Intercept 303.85 135.61 2.240 0.026
BMI 35.22 55.62 0.633 0.527
Day −1.45 1.16 −1.249 0.212
BMI*day 0.12 0.47 0.263 0.793
Model 1Ba Intercept 336.44 51.77 6.499 0.000
Pre-COVID 448.14 142.83 3.137 0.002
Day −1.06 0.39 −2.653 0.009
Pre-COVID*day −1.55 1.07 −1.441 0.153
Model 1C Intercept 413.64 39.48 10.478 0.000
Comorbidities −136.11 80.66 −1.687 0.092
Day −1.48 0.34 −4.343 0.000
Comorbidities*day 1.81 0.76 2.391 0.017
Model 1Da Intercept 69.24 127.32 5.469 0.000
Age −280.97 110.91 −2.533 0.012
Day −3.62 1.48 −2.440 0.015
Age*day 2.27 1.38 1.646 0.100
Model 1E Intercept 518.89 151.22 3.431 0.001
Gender −80.57 94.26 −0.855 0.394
Day −1.66 1.12 −1.480 0.141
Gender*day 0.28 0.71 0.391 0.696
Model 1F Intercept 342.76 93.31 3.673 0.000
Group 24.71 49.83 0.496 0.620
Day −0.50 0.81 −0.617 0.537
Group*day −0.40 0.45 −0.887 0.376
  1. aFixed effect variables in model 1B and 1D (prior COVID and age) had significant main effect on the antibody titer values in univariate analysis.

Table 6:

Summary table of multivariable analysis.

Parameter Estimate SE t-Value p-Value
Intercept 611.014 127.6748 4.786 0.000
Pre-COVID 383.302 99.3376 3.859 0.000
Age −247.654 109.499 −2.262 0.024
Day −3.3859 1.5011 −2.256 0.024
Pre-COVID*day −1.0673 0.8675 −1.230 0.219
Age*day 2.1524 1.3788 1.561 0.119
  1. Kenward Roger R2=0.25; Fixed effect variables in the final model (prior COVID and age) showed significant main effect on the antibody titer values in multivariable analysis.

Figure 1: 
Antibody response in different subgroups. Box plots showing median (range) of log antibody titers on each sampling day. The solid line connecting the plots corresponds to mean antibody titer for each timepoint. The individual dots represent antibody titers of each participant sampled on respective days. The number of observations contributing to each box plot is provided in Supplementary Tables (S2 and S6). Antibody titer in participants without previous COVID infection (A1) (n=452) and those with previous COVID infection (A2) (n=60) is shown. Antibody titer in participants <60 years of age (B1) (n=468) and ≥60 years of age (B2) (n=44) is shown. Log antibody titer on the y-axis is plotted against days since first dose of vaccination on the x-axis.
Figure 1:

Antibody response in different subgroups. Box plots showing median (range) of log antibody titers on each sampling day. The solid line connecting the plots corresponds to mean antibody titer for each timepoint. The individual dots represent antibody titers of each participant sampled on respective days. The number of observations contributing to each box plot is provided in Supplementary Tables (S2 and S6). Antibody titer in participants without previous COVID infection (A1) (n=452) and those with previous COVID infection (A2) (n=60) is shown. Antibody titer in participants <60 years of age (B1) (n=468) and ≥60 years of age (B2) (n=44) is shown. Log antibody titer on the y-axis is plotted against days since first dose of vaccination on the x-axis.

Effectiveness of the vaccine

The effectiveness of ChAdOx1 nCoV-19 based on the interval between doses was determined using Kaplan-Meier plots. Volunteers in group 2 and group 3 were pooled into a common set and compared with group 1 for time to onset of breakthrough COVID infection. Four hundred and forty-two volunteers were included in this analysis of which 208 belonged to group 1 and 234 belonged to the pooled set of groups 2 and 3. At the median follow-up of 10 (range 7–11) months, the breakthrough COVID free survival was higher in the pooled group compared to group 1 (HR=0.51 (0.25–1.04); p=0.06) (Figure 2). In addition, we sought to find out whether the additional waiting time for the second dose in groups 2 and 3 made the vaccinees vulnerable for COVID. Therefore, another set of survival analysis was carried out starting from day 22 after the first dose, excluding vaccinees who had COVID prior to vaccination and up to day 21 following the first dose. Here again, group 2, 3 had significantly better protection from vaccination compared to group 1 (HR=0.46 (0.22–0.99; p=0.04). Interestingly, despite having higher antibody titers, no difference in the incidence of breakthrough infection was observed in participants with or without previous COVID infection (3/60 vs. 24/442). Similarly, no difference in breakthrough rates was observed in participants aged <60 years or >60 years (22/401 vs. 2/41). None of the COVID positive cases diagnosed at least 21 days after the first dose (n=29) of the vaccine required hospitalization, and all of them recovered at home with mild-moderate symptoms.

Figure 2: 
COVID free survival. Kaplan-Meier plots with 95 % CI showing COVID-free survival post day 14 of the second dose is shown. Group 1 received the second dose at an interval of 4 weeks after the first dose. Group 2, 3 is a combined representation of participants who received the second dose at an interval of 6 weeks or later. Participants who were diagnosed with COVID prior to vaccination and until day 14 of the second dose were excluded from analysis. Hazard ratio was calculated by Cox proportional hazard assumption (HR=0.51 (0.25–1.04); p=0.06). The y-axis has been truncated for better visualization of COVID-free survival in the two groups.
Figure 2:

COVID free survival. Kaplan-Meier plots with 95 % CI showing COVID-free survival post day 14 of the second dose is shown. Group 1 received the second dose at an interval of 4 weeks after the first dose. Group 2, 3 is a combined representation of participants who received the second dose at an interval of 6 weeks or later. Participants who were diagnosed with COVID prior to vaccination and until day 14 of the second dose were excluded from analysis. Hazard ratio was calculated by Cox proportional hazard assumption (HR=0.51 (0.25–1.04); p=0.06). The y-axis has been truncated for better visualization of COVID-free survival in the two groups.

Discussion

We have presented data on the reactogenicity, antibody response and effectiveness of ChAdOx1 nCoV-19 vaccine in a real-world setting, in a population of healthcare workers, frontline workers and general public. During the course of the study, the Government of India changed its policies on the interval between the two doses of the vaccine from 4 weeks to 6–8 weeks and later to more than 12 weeks. The study period also coincided with the peak of COVID infections due to B.1.617.2, commonly known as the delta variant of SARS-CoV-2 virus [11]. Thus, we were in a unique position to assess the performance of the vaccine while the second wave of the pandemic was unfolding, amid changing policies.

The total number of participants reporting adverse events in our study was 29.5 % for local events and 46.1 % for systemic events which is in the lower end of the range when compared to 40–83 % for local adverse reactions and 37–72 % for systemic adverse reactions reported in previous studies [1, 6, 9, 12, 13]. Of the total adverse events observed in our study, 96.3 % were mild to moderate and are comparable to 92–100% reported in other studies [1, 14]. Three events qualified as serious adverse events by virtue of requiring hospitalisation, the incidence was comparable with 0.2–0.7 % reported in earlier studies [6, 14, 15]. The commonest adverse effects observed in our study were injection site pain, fever, headache and myalgia and were similar to those observed during the phase 1/2 and 2/3 clinical trials [1, 7]. An approximate 35 % drop in the incidence of adverse events was observed following the second dose compared to the first. This finding was consistent with earlier studies [2, 12]. We did not encounter any new adverse events in our study and the reported events were mostly mild to moderate. Thrombotic events such as thrombosis and thrombocytopenia have been reported in some studies as adverse events of concern [5, 16], [17], [18], [19]. However, no such serious adverse events were reported in our study till the cut-off date. Female sex, age <60 years and presence of comorbidities had significantly higher systemic adverse reactions compared to their counterparts. Similar findings were reported by Kaur et al. in their observational study [15]. Incidence of systemic reactions to ChAdOx1 nCoV-19 is known to be higher in younger age group [7]. Females are known to show a greater antibody response and B cell levels compared to males in the event of immune stimulation [19]. At the same time, immunity is known to wane with age [20]. The variable immune response to the vaccine may explain the differences in systemic toxicity between these subsets of population.

Neutralizing antibodies offer protection against SARS-CoV-2 infection as shown by various vaccine effectiveness studies [21, 22]. Although the effect on immunity against SARS-CoV-2 infection due to waning antibody titers, or the exact level of antibody titer needed for this protection is not clearly understood, it appears that there may be correlation between high levels of nAB and protection against infection [21, 22]. It has been observed that antibodies that target and bind to the S1 RBD, which were measured in this study, have demonstrated strong correlation to neutralization [1].

In our study, 100 % of participants were reactive for these antibodies. This result concurs with those observed in a phase 1/2 trial of the vaccine with 543 participants [1], and a phase 2/3 trial of the vaccine conducted on 560 participants [7], both of which showed 100 % antibody response after first and second doses of the vaccine. A smaller study by Tenbusch et al. [23] (n=66) demonstrated 98.5 % reactivity after the second dose. On the other hand, Singh et al. reported a slightly lower seropositivity of 86.8 % among 425 volunteers after the first dose which increased to 98 % following the second dose [12]. The findings of our study indicate that the vaccine is able to elicit an immune response in recipients after the first dose itself. Significantly, the interval between the first and the booster dose showed no effect on the antibody titer levels till day 180.

Various studies have been conducted to establish the effects of demographical parameters such as age, BMI, gender, comorbidities etc. on the antibody titer. Similarly other studies have found antibody response in older adults to be lower than younger participants [2426]. In addition previous COVID infection was found to influence the antibody titer in vaccine recipients [27]. Our study corroborated these findings, and multivariable analysis showed that previous SARS-CoV-2 infection and age <60 years favoured a stronger Ab response. There was no effect of sex, pre-existing comorbidities, or BMI on the titer of AB in participants of our study. It should be noted that the R-squared was only 0.25, indicating 75 % of the variability in titer values could not be explained by the model. This indicates that, further studies can emphasis on including and evaluating the influence of other covariates on antibody titres.

An overall infection rate of 6.4 % was observed among the vaccinees, all cases being mild to moderate in severity, not requiring hospitalization. We did not include previously SARS-CoV-2 infected individuals in time to failure analysis since they are known to have humoral protection against COVID infection which could have confounded the outcomes. The time to failure of vaccination was shorter in volunteers who received the second dose at an interval of four weeks, compared to those with longer spacing between doses. This finding also concurs with the findings of an earlier trial of ChAdOx-1 nCoV-19 where the vaccine effectiveness at 3 months interval was shown to have advantage over shorter intervals [6]. It was also observed by Kaur et al. in a larger study of 1,500 participants that the odds of getting infection were greater at 6.7 times in those who had a ≤30 days duration between the two doses [28]. This may be attributed to the possibility that the humoral immunity generated by the second dose of vaccine wanes off faster when the doses are given at close intervals. The first dose generates a primary response which leads to B cells recognising the antigen presented as a pathogen. This humoral response of memory cells wanes over time. The second dose generates a faster and more effective response to the antigen presented. It is possible that in the case of increased interval of 6 weeks of more, probably the humoral immunity induced by the second dose gives protection for a longer time [10, 29].

We did not find any difference between the rate of breakthrough infection in those with previous COVID compared to those without previous COVID infection. Similar observations were also made by Kaur and colleagues in an observational study [28]. An analysis of the pooled data from the clinical trials conducted in UK, Brazil and South Africa showed lower vaccine effectiveness in participants having one or more comorbidity [6]. No such evidence for breakthrough COVID infection with respect to comorbidities was observed in our study.

The limitation of this study was that it was a single center study in a small population of vaccinees. Incidence of COVID infection is also dependent on COVID-appropriate behavior, and evidently, we did not have control over it. However, it is safe to assume that such behavior is likely to be randomly distributed across the groups, and therefore may not be a major confounder. Besides, the vaccination program coincided with the second wave of the pandemic in India when COVID appropriate behavior was being continuously emphasized and reiterated in the media and workplaces. Secondly, we were not able to have a control group of non-vaccinated individuals, thus comparison between the two groups for effectiveness of the vaccine could not be done. Finally, we used a convenient sampling strategy to study antibody response which at best reflects the general trend in the population and not necessarily provide reliable estimates owing to inherent biases. However, it is an acceptable approach in real world evidence studies as opposed to the controlled settings of a clinical trial [30]. The strengths included that the participants were a mix of front-line workers, students and general public which adequately represented the cross-section of society. The follow-up was adequate; median 10 months after the first dose, and information related to breakthrough and nature and severity of adverse events could be accurately documented. Finally, since the study was set in the peak of second COVID wave in India, we were able to ascertain the effectiveness of vaccine in an actual pandemic setting.

Conclusions

The ChAdOx1 nCov-19 vaccine is apparently safe and effective against SARS-CoV-2 virus infection. Prior COVID infection and younger age group achieve higher antibody titers, but no additional protection. Delaying the second dose up to at least 6 weeks is more effective compared to shorter spacing between doses. Countries where vaccination rates are low due to several logistical reasons can consider extending the interval for second dose up to 12 weeks or beyond, thus being able to vaccinate a larger population with at least one dose of the vaccine.


Corresponding author: Dr. Vikram Gota, MD, Professor, Department of Clinical Pharmacology, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Sector-22, Kharghar, Navi Mumbai 410210, India; and Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India Phone: +91 22 27405130, E-mail:

Funding source: Indian Council of Medical Research

Award Identifier / Grant number: 55/4/13/CARE-CP/2018-NCD-II

Funding source: Departmental funds for Composite Laboratory at the Advanced Centre for Treatment, Research and Education in Cancer (ACTREC)

  1. Research funding: The study was funded by the Indian Council of Medical Research (Grant No. 55/4/13/CARE-CP/2018-NCD-II); and the departmental funds for Composite Laboratory at the Advanced Centre for Treatment, Research and Education in Cancer (ACTREC).

  2. Author contributions: VG, PC and VB conceived and designed the study. VG and PC acquired funding for the study. AK, MJ, AS, AC, SD, RC, MN and VG enrolled volunteers for antibody testing. RM, PP, PC and VB conducted the antibody testing. AB,RD and SK carried out the statistical analysis. PC prepared the first draft of the manuscript. RC, AB, VB and VG reviewed the draft. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individual participants included in the study.

  5. Ethical approval: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013), and has been approved by the authors’ Institutional Review Board (TMC-ACTREC IEC-III, Registration number: ECR/149/Inst/MH/2013).

References

1. Folegatti, PM, Ewer, KJ, Aley, PK, Angus, B, Becker, S, Belij-Rammerstorfer, S, et al.. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020;396:467–78. https://doi.org/10.1016/s0140-6736(20)31604-4.Search in Google Scholar

2. Vaxzevria induced immunity for at least one year following a single dose and strong immune responses following either a late second dose or a third dose [Internet]. Available from: https://www.astrazeneca.com/media-centre/press-releases/2021/vaxzevria-induced-immunity-for-at-least-1-year-following-a-single-dose-and-strong-immune-responses-following-either-a-late-second-dose-or-a-third-dose.html [cited May 9 2022].Search in Google Scholar

3. Flaxman, A, Marchevsky, NG, Jenkin, D, Aboagye, J, Aley, PK, Angus, B, et al.. Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002). Lancet 2021;398:981–90. https://doi.org/10.1016/s0140-6736(21)01699-8.Search in Google Scholar PubMed PubMed Central

4. European database of suspected adverse drug reaction reports (EudraVigilance) - Data Europa EU [Internet]. Available from: https://data.europa.eu/data/datasets/suspected-adverse-drug-reaction-reports?locale=en [cited May 9 2022].Search in Google Scholar

5. Tobaiqy, M, Elkout, H, MacLure, K. Analysis of thrombotic adverse reactions of COVID-19 AstraZeneca vaccine reported to EudraVigilance database. Vaccines (Basel) 2021;9:393. https://doi.org/10.3390/vaccines9040393.Search in Google Scholar PubMed PubMed Central

6. Voysey, M, Clemens, SAC, Madhi, SA, Weckx, LY, Folegatti, PM, Aley, PK, et al.. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021;397:99–111. https://doi.org/10.1016/s0140-6736(20)32661-1.Search in Google Scholar

7. Ramasamy, MN, Minassian, AM, Ewer, KJ, Flaxman, AL, Folegatti, PM, Owens, DR, et al.. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet 2021;396:1979–93. https://doi.org/10.1016/s0140-6736(20)32466-1.Search in Google Scholar

8. US Department of Health and Human Services. Common terminology criteria for adverse events. Version 5; 2017. Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_8.5x11.pdf.Search in Google Scholar

9. Voysey, M, Costa Clemens, SA, Madhi, SA, Weckx, LY, Folegatti, PM, Aley, PK, et al.. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet 2021;397:881–91. https://doi.org/10.1016/s0140-6736(21)00432-3.Search in Google Scholar

10. CDC. COVID-19 vaccination [Internet]. Centers for Disease Control and Prevention; 2020. Available from: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/effectiveness/why-measure-effectiveness/breakthrough-cases.html. [cited 2022 May 9].Search in Google Scholar

11. Thangaraj, JWV, Yadav, P, Kumar, CG, Shete, A, Nyayanit, DA, Rani, DS, et al.. Predominance of delta variant among the COVID-19 vaccinated and unvaccinated individuals, India, May 2021. J Infect 2022;84:94–118. https://doi.org/10.1016/j.jinf.2021.08.006.Search in Google Scholar PubMed PubMed Central

12. Singh, AK, Phatak, SR, Singh, R, Bhattacharjee, K, Singh, NK, Gupta, A, et al.. Antibody response after first and second-dose of ChAdOx1-nCOV (CovishieldTM®) and BBV-152 (CovaxinTM®) among health care workers in India: the final results of cross-sectional coronavirus vaccine-induced antibody titre (COVAT) study. Vaccine 2021;39:6492–509. https://doi.org/10.1016/j.vaccine.2021.09.055.Search in Google Scholar PubMed PubMed Central

13. Falsey, AR, Sobieszczyk, ME, Hirsch, I, Sproule, S, Robb, ML, Corey, L, et al.. Phase 3 safety and efficacy of AZD1222 (ChAdOx1 nCoV-19) covid-19 vaccine. N Engl J Med 2021;385:2348–60. https://doi.org/10.1056/nejmoa2105290.Search in Google Scholar PubMed PubMed Central

14. Kaur, RJ, Dutta, S, Bhardwaj, P, Charan, J, Dhingra, S, Mitra, P, et al.. Adverse events reported from COVID-19 vaccine trials: a systematic Review. Indian J Clin Biochem 2021;36:427–39. https://doi.org/10.1007/s12291-021-00968-z.Search in Google Scholar PubMed PubMed Central

15. Kaur, U, Ojha, B, Pathak, BK, Singh, A, Giri, KR, Singh, A, et al.. A prospective observational safety study on ChAdOx1 nCoV-19 corona virus vaccine (recombinant) use in healthcare workers- first results from India. EClinicalMedicine 2021;38:101038. https://doi.org/10.1016/j.eclinm.2021.101038.Search in Google Scholar PubMed PubMed Central

16. EMA. AstraZeneca’s COVID-19 vaccine: benefits and risks in context [Internet]. European Medicines Agency; 2021. Available from: https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-benefits-risks-context. [cited May 9 20223].Search in Google Scholar

17. Schultz, NH, Sørvoll, IH, Michelsen, AE, Munthe, LA, Lund-Johansen, F, Ahlen, MT, et al.. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med 2021;384:2124–30. https://doi.org/10.1056/nejmoa2104882.Search in Google Scholar PubMed PubMed Central

18. Scully, M, Singh, D, Lown, R, Poles, A, Solomon, T, Levi, M, et al.. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N Engl J Med 2021;384:2202–11. https://doi.org/10.1056/nejmoa2105385.Search in Google Scholar

19. Klein, SL, Flanagan, KL. Sex differences in immune responses. Nat Rev Immunol 2016;16:626–38. https://doi.org/10.1038/nri.2016.90.Search in Google Scholar PubMed

20. Simon, AK, Hollander, GA, McMichael, A. Evolution of the immune system in humans from infancy to old age. Proc Biol Sci 2015;282:20143085. https://doi.org/10.1098/rspb.2014.3085.Search in Google Scholar PubMed PubMed Central

21. Chia, WN, Zhu, F, Ong, SWX, Young, BE, Fong, SW, Le Bert, N, et al.. Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study. Lancet Microbe 2021;2:e240–9. https://doi.org/10.1016/s2666-5247(21)00025-2.Search in Google Scholar PubMed PubMed Central

22. Cromer, D, Steain, M, Reynaldi, A, Schlub, TE, Wheatley, AK, Juno, JA, et al.. Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis. Lancet Microbe 2021;3:52–61. https://doi.org/10.1016/S2666-5247(21)00267-6.Search in Google Scholar PubMed PubMed Central

23. Tenbusch, M, Schumacher, S, Vogel, E, Priller, A, Held, J, Steininger, P, et al.. Heterologous prime-boost vaccination with ChAdOx1 nCoV-19 and BNT162b2. Lancet Infect Dis 2021;21:1212–3. https://doi.org/10.1016/s1473-3099(21)00420-5.Search in Google Scholar

24. Collier, DA, Ferreira, IATM, Kotagiri, P, Datir, RP, Lim, EY, Touizer, E, et al.. Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2. Nature 2021;596:417–22. https://doi.org/10.1038/s41586-021-03739-1.Search in Google Scholar PubMed PubMed Central

25. Anderson, EJ, Rouphael, NG, Widge, AT, Jackson, LA, Roberts, PC, Makhene, M, et al.. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med 2020;383:2427–38. https://doi.org/10.1056/nejmoa2028436.Search in Google Scholar

26. Li, J, Hui, A, Zhang, X, Yang, Y, Tang, R, Ye, H, et al.. Safety and immunogenicity of the SARS-CoV-2 BNT162b1 mRNA vaccine in younger and older Chinese adults: a randomized, placebo-controlled, double-blind phase 1 study. Nat Med 2021;27:1062–70. https://doi.org/10.1038/s41591-021-01330-9.Search in Google Scholar PubMed

27. Anichini, G, Terrosi, C, Gandolfo, C, Gori Savellini, G, Fabrizi, S, Miceli, GB, et al.. SARS-CoV-2 antibody response in persons with past natural infection. N Engl J Med 2021;385:90–2. https://doi.org/10.1056/nejmc2103825.Search in Google Scholar

28. Kaur, U, Bala, S, Ojha, B, Pathak, BK, Joshi, A, Yadav, AK, et al.. Determinants of COVID-19 breakthrough infections and severity in ChAdOx1 nCoV-19-vaccinated priority groups. Am J Trop Med Hyg 2022;107:850–5. https://doi.org/10.4269/ajtmh.22-0172.Search in Google Scholar PubMed PubMed Central

29. Clem, AS. Fundamentals of vaccine immunology. J Glob Infect Dis 2011;3:73–8. https://doi.org/10.4103/0974-777x.77299.Search in Google Scholar

30. Jager, J, Putnick, DL, Bornstein, MH. Ii. More than just convenient: the scientific merits of homogeneous convenience samples. Monogr Soc Res Child Dev 2017;82:13–30. https://doi.org/10.1111/mono.12296.Search in Google Scholar PubMed PubMed Central


Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/dmpt-2022-0150).


Received: 2022-06-30
Accepted: 2023-01-23
Published Online: 2023-04-26

© 2023 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 28.3.2024 from https://www.degruyter.com/document/doi/10.1515/dmpt-2022-0150/html
Scroll to top button