COVAT-2: Clear message – Both Indian vaccines doing great

CME INDIA Presentation by Admin.

“COVAT- 2 got preprint version (Not peer-reviewed) published on 4rth of June 2021 and its message spread like a wild fire. The study found good antibody response in 95% of the study participants 21 days after they received the second dose of the vaccine. Both vaccines yielded very good seropositivity – it was 98% in Covishield recipients and 80% in Covaxin recipients. A very illuminating finding also emerged in favour of Covaxin. Breakthrough infections SARS-CoV-2 infection >2 weeks after the second dose were noted in 5.5% cohorts in Covishield and 2.2% of Covaxin recipients. Overall this study clearly tells us to expedite the vaccination drive to protect masses and will further remove the misconceptions against vaccination.”

Title of the Study

Antibody Response after Second-dose of ChAdOx1-nCOV (CovishieldTM®) and BBV-152 (CovaxinTM®) among Health Care Workers in India: Final Results of Cross-sectional Coronavirus Vaccine-induced Antibody Titre (COVAT) study.

Authors:

• Dr Awadhesh Kumar Singh, MD, DM (Kolkata) (Main author);
• Dr Sanjeev Ratnakar Phatak, MD (Ahmedabad) (Principle investigator);
• Dr Ritu Singh, MD (Kolkata);
• Dr Kingshuk Bhattacharjee, PhD (Kolkata);
• Dr Nagendra Kumar Singh (NK Singh), (Dhanbad);
• Dr Arvind Gupta, MD (Jaipur);
• Dr Arvind Sharma, MD (Jaipur);

Regional Investigators

Drs. – Akash Kumar Singh (Vadodara), Amit Gupta (Noida), Anuj Maheshwari (Lucknow), Arvind Kumar Ojha (Kolkata), Bhavtharini (Erode), B. Harish Kumar (Mysore), J K Sharma (New Delhi), Jayant Panda (Cuttack), Kavya Chand Yalamudi (Guntur), Kiran Shah (Vadodara), M Gowri Sankar (Coimbatore), Manohar KN (Bangalore), Meena Chhabra (New Delhi), Pratap Jethwani (Rajkot), M Shunmugavelu (Trichy), Rajiv Kovil (Mumbai), Sunil Gupta (Nagpur), Subhash Kumar (Patna), Somnath (Hyderabad) and Urman Dhruv(Ahmedabad) are involved in this study as regional co-ordinators.

Why done?

• While, early data from available phase 3 randomized clinical trials (RCTs) suggested that these two vaccines are safe and effective , there is still a paucity of information as to how much and how long, these novel vaccines can elicit an immune response, humoral and cellular level in real-world settings.
• The preliminary results of ongoing Cross-sectional Coronavirus Vaccine-induced Antibody Titre (COVAT) study that assessed the anti-spike antibody humoral response 21-day after the first dose but before the second dose of both Covishield and Covaxin have been reported earlier.
• Now  binding anti-spike antibody kinetics after the completion of second dose of two vaccines from the ongoing COVAT study has been published in Medrxiv on 4 rth June. (The study has not yet been peer reviewed).

COVAT study is an ongoing, PAN-India, cross-sectional study

• Data collection for this analysis started since the January 16, 2021 (first day of vaccination amongst HCW) until May 15, 2021 (data-lock date).
• Anti-spike antibody titre is being measured at four timepoints
  1. Day 21 after the first dose until the day before the second dose.
  2. Day 21-28 of second dose, second blood samples (5 ml) were collected from eligible from day 21-36 after the second dose of each vaccine.
  3. Day 83-97 (3-months).
  4. Day 173-187 (6-months) after the second dose.

What was done?

• The IgG antibodies to SARS CoV-2 directed against the spike protein (S-antigen, both S1 and S2 protein) were assayed with LIASON® S1/S2 quantitative antibody detection kit (DiaSorin Saluggia, Italy) using indirect chemiluminescence immunoassay (CLIA).
• The diagnostic sensitivity of this kit has been reported to be 97.4% (95% Confidence Interval [CI], 86.8-99.5%) >15 days after SARS-CoV-2 infection with a specificity of 98.5% (95% CI, 97.5-99.2%) as per manufacturer’s protocol.
• Antibody levels >15.0 arbitrary unit (AU)/mL were considered as sero-positive, while antibody level ≤15 AU/mL are considered as seronegative, as per manufacturer’s kit.
• This kit has found to have a concordance to neutralizing antibody (NAb) done by Plaque Reduction Neutralization Test (PRNT) with a positive agreement of 94.4% (95% CI, 88.8-97.2%) and negative agreement of 97.8% (95% CI, 94.4-99.1%) at a cut-off of >15 AU/mL. The lower and upper limit of this quantitative spike antibody kit is 3.8 and 400 AU/mL respectively, as per manufacture’s brochure.

What has been found?

• Five hundred and fifteen participants who received second dose of either of the two vaccines, had complete set of data including anti-spike antibody.
• The mean age of the participants was 44.8 ± 13.1 years, with 59.2% males (305/515) and 40.8% females (210/515).
• Overall, 95.0% (489/515) had seropositivity (defined as anti-spike antibody titre >15AU/mL measured at day 21-36 after the second dose) for anti-spike antibody.
• Out of 515 participants, 437 (84.9%) were aged ≤ 60 years and 78 (15.1%) were of age > 60 years.
• While 24.3% (125/515) had one or more comorbidities, 10.1% had T2DM, 18.3% had HTN, 4.7% had dyslipidemia and 2.5% had IHD.
• There was no participant having T1DM, CKD or cancer in our study cohort.
• Among all participants, 11.3% (58/515) had past history of confirmed SARS-CoV2 (2-week prior to the first dose of vaccine) – who completed two doses of either of the vaccine.

SARS-COV-2 spike antibody positivity rates after first dose of two vaccine

• A total of 515 (305 male, 210 female) participants’ data was analyzed.
• Out of these 425 and 90 had received both doses of Covishield and Covaxin respectively.
• Overall, 95.0% (489/515) had seropositivity (defined as anti-spike antibody titre >15AU/mL measured at day 21-36 after the second dose) for anti-spike antibody.
• Notably, the seropositivity rate was significantly higher in Covishield vs. Covaxin recipients (98.1 vs. 80.0% respectively, p60 years (87.2%), in overall cohorts, primarily contributed by Covishield recipients.
• While no difference in seropositivity rate was observed for gender, BMI and presence of any comorbidities in overall cohorts between the two arms, females compared to males (100.0 vs. 96.8%, p=0.02).

• People with BMI 25 Kg/m2 (99.3 vs. 95.7%, p=0.03) and the presence of any comorbidities compared to those without (95.6 vs. 99.0%, p=0.02), had a significantly higher seropositivity rate in Covishield arm.
• Amongst the captured co-morbidities, people with T2DM had a significantly lower seropositivity rate compared to those without (84.6 vs. 96.1%, p=0.002) in overall cohort, and this was consistent in both Covishield (91.3 vs. 98.9%), and this was consistently observed in both Covishield and Covaxin recipients.
• No difference of seropositivity rate was observed in people with HTN.

It additionally analyzed the seropositivity rate after excluding SARS-CoV-2 recovered

• The study also additionally analyzed the seropositivity rate after excluding SARS-CoV-2 recovered (n=58) cohorts.
• Importantly, in this analysis of 457 cohorts’ results were similar and consistent. Seropositivity rate after the two complete doses was significantly higher in Covishield compared to Covaxin recipients (97.8 vs. 79.3%; p <0.001).

Comparison of SARS-CoV-2 spike antibody between Covishield and Covaxin after propensity matched analysis

(Propensity score matching (PSM) is a quasi-experimental method in which the researcher uses statistical techniques to construct an artificial control group by matching each treated unit with a non-treated unit of similar characteristics. Using these matches, the researcher can estimate the impact of an intervention.)

• In the propensity-matched analysis of 116 SARS-CoV-2 naïve cohorts (58 participants in each arm) after the adjustment for age, sex and BMI; seropositivity rates were significantly higher in Covishield arm compared to the Covaxin (98.3% vs. 82.8%, p=0.004).
• Age ≤60 years had a higher seropositivity rate vs. >60-years (98.5 vs. 79.6%, p=0.001) and presence of T2DM was associated with a lesser seropositivity rate compared to those without (92.0 vs. 50.0%, p=0.005).

Assessment of SARS-CoV-2 spike antibody quantity after two complete doses of Covishield and Covaxin

• The median (IQR) rise in anti-spike antibody was significantly higher (p<0.001) in Covishield recipients 127.0 (70.5-268.5) AU/mL, compared to Covaxin arm 53.0(22.3-131.0) AU/mL. (Note: To find the interquartile range (IQR), ​first we find the median (middle value) of the lower and upper half of the data. These values are quartile 1 (Q1) and quartile 3 (Q3). The IQR is the difference between Q3 and Q1).
• Significantly higher median values of anti-spike antibody were observed in people having age ≤60 vs. >60 years (120.0 vs. 92.0 AU/mL, p=0.03), primarily skewed by higher value in Covishield arm (131.0 vs. 113.0AU/mL respectively, p=0.03). In the overall cohort, the females had a significantly higher median antibody titre compared to the males (131.0 vs. 112.0 AU/mL, p=0.01), primarily driven by Covishield arm.
• Although presence of any comorbidities was not associated with any differential antibody titre, presence of HTN was associated with a significantly attenuated median antibody titre compared to those without (95.0 vs. 124.0 AU/mL, p=0.002), particularly in the Covishield arm. Indeed, past history of SARS-CoV-2 infection elicited a significantly greater median antibody titre, compared to SARS-CoV-2 naïve cohorts (400.0 vs. 110.0 AU/mL, p <0.001), irrespective of the type of vaccine received.
• Box and whisker plot depicts the log antibody titre for different study parameters that were significantly different after the two complete doses of vaccines (Box and whisker plots are ideal for comparing distributions because the centre, spread and overall range are immediately apparent. A box and whisker plot is a way of summarizing a set of data measured on an interval scale).

• The median (IQR) rise in anti-spike antibody titre was significantly higher in Covishield recipients compared to Covaxin (115.5 vs. 51.0 AU/mL, p <0.001), 21-36 days after the completion of second dose in SARS-CoV-2 naïve participants.

Post-vaccination SARS-CoV-2 infection

• From Jan 16, 2021 (Day 1 of vaccination) until May 15, 2021 (Day 21-36 after second dose, data-locking date), a total of 30 (30/492, 6.1%) HCW have reported to have COVID-19 among SARS-CoV-2 naïve cohorts (n=492) after the first dose of vaccination.
• Of the 30 participants 4 had suspected (symptomatic and positive HRCT signs but negative to either RT-PCR or RAT) and 26 had confirmed (RTPCR or RAT positive) COVID-19.
• Three had SARS-CoV-2 infection before the second dose, while 27 had acquired SARS-CoV-2 infection after the second dose.
• Breakthrough infections (defined as SARS-CoV-2 infection >2 weeks after the second dose) were reported in 4.9% (24/492) of cases following both vaccines.
• Breakthrough infections were noted in 5.5% (22/399) cohorts in Covishield and 2.2% (2/93) of Covaxin recipients. Majority had mild (28/30) to moderate (2/30) COVID-19 infections and all recovered. None of the cohort who had COVID-19 following either vaccine had severe COVID requiring mechanical ventilation.

CME INDIA Learning Points

• COVAT study reported an overall 95.0% (489/515) seropositivity rate after the two complete doses of both vaccines in entire cohorts that include both SARS-CoV-2 naïve and recovered individuals.
• Seropositivity rates after two complete doses was 97.8% and 79.3% with Covishield and Covaxin, respectively in SARSCoV-2 naïve individuals.
• 100% of cohorts with a past history of SARS-CoV-2 were seropositive after the two doses of both vaccines.
• Covaxin gained a significant increase in both seropositivity and antibody titre only after the two completed doses.
• Covishield showed a good seropositivity rate and a 4-fold rise in median antibody titre even after a single dose.
• One dose of either vaccine yielded a very high seropositivity and anti-spike antibody titre in SARS-CoV-2 recovered individuals
• There was no significant difference in seropositivity rate with regard to age, sex, BMI, blood group.
• The participants with T2DM and T2DM or HTN of >5-year duration had a significantly less seropositive rate compared to those without.

• In age-, sex- and BMI-matched propensity analysis, seropositivity rate and median anti-spike antibody titre was significantly higher with Covishield compared to Covaxin in SARS-CoV-2 naïve recipients.
• Sex, presence of comorbidities, and type of vaccine used were an independent predictor of antibody response in multiple regression analysis.
• The larger question is whether humoral antibody response to a vaccine correlates with the efficacy (reduction in severity and mortality due to COVID-19). Although the correlation of antibody titre to the vaccine efficacy is less well understood, Nab targeting different epitopes of spike glycoprotein have been found to protect from COVID-19 with ChAdOx1 nCoV-19 (Covishield) and Moderna mRNA-1273 vaccine
• Moreover, NAb titre following vaccination was highly correlated with the NAb titre in convalescent post-SARS-CoV-2 infection. Furthermore, Antispike antibody titre is reported to highly correlate with in-vitro virus neutralization test measured by PNT .
• Collectively, it is not exactly known as to what level of binding and neutralizing antibody protects human from COVID-19 .
• This Pan-India cross-sectional COVAT study would be the first of its kind that has involved HCW from 13 States and 22 cities and reporting anti-spike antibody kinetics after two completed doses of two different vaccines.
• Limitations:
  • A convenience sampling amounting to selection bias.
  • This study used a binary logistic regression (to identify the predictors of non-response to vaccines) which primarily assumes linearity between the explanatory variable and the outcome variable, hence this model may miss out any predictor variable which may have non-linear relationship with the outcome variable.
  • This study measured only anti-spike binding antibody and could not assess NAb and cell-mediated immune response such as Th-1 and Th-2 dependent antibody or cytokines
  • This study did not measure the baseline anti-spike antibody titre prior to the vaccination, because of logistic issue due to lockdown.
  • Two value of short-term anti-spike antibody as evaluated in this report may not necessarily predict the efficacy of vaccine, nor the absence of seropositivity confer failure of vaccine in absence of NAb and T-cell response assessment.
• The study concludes – “This cross-sectional study after the completion of two doses of both vaccines suggests that both vaccines induce seropositivity to anti-spike antigen in 95% of SARS-COV-2 naïve and recovered individuals after 3-weeks. Whether any real difference in inducing immunogenicity exists between two vaccines can only be meaningfully demonstrated through a head-to-head RCT.”

CME INDIA Tail Piece

1. Media must restrain from spreading wrong messages. Both vaccines are doing excellent job and are vital in adopting national policy. Lesser number of Post vaccination covid cases in Covaxin arm speaks a lot about it.

2. As per business standard, Samiran Panda, head of epidemiology and communicable division at the Indian Council of Medical Research says:

• Antibody developed or not developed is a binary variable (above a predefined laboratory cut-off). However, what is the result from a quantitative comparison – also needs to be examined – is the difference between the mean or median titre between the two groups.
• Any arbitrary draw of a sample brings in a bias and does not allow extrapolation of inference on a larger universe of people.
• Moreover,immunity is not only guided by the humoral arm of immunity but also the cellular arm.

3. These limitations of the study have been well explained by authors in the discussion part of the study.

4. For Media:

Reference:

1. Antibody Response after Second-dose of ChAdOx1-nCOV (Covishield™®) and BBV-152 (Covaxin™®) among Health Care Workers in India: Final Results of Cross-sectional Coronavirus Vaccine-induced Antibody Titre (COVAT) study Awadhesh Kumar Singh, Sanjeev Ratnakar Phatak, Ritu Singh, Kingshuk Bhattacharjee, Nagendra Kumar Singh, Arvind Gupta, Arvind Sharma medRxiv 2021.06.02.21258242; doi: https://doi.org/10.1101/2021.06.02.21258242

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