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Clinical profile of ChAdOx1 nCoV-19- and BBV152-vaccinated individuals among hospitalized COVID-19 patients: a pair-matched study

Background: COVID-19 infections among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-vaccinated individuals are of clinical concern, especially in those requiring hospitalization. Such real-world data on ChAdOx1 nCoV-19- and BBV152-vaccinated individuals are scarce. Hence, there is an urgent need to understand their clinical profile and outcomes. Methods: A 1:1 pair-matched study was performed among vaccinated and unvaccinated COVID-19 patients admitted between March 2021 and June 2021 at a tertiary care centre in New Delhi, India. The vaccinated group (received at least one dose of ChAdOx1 nCoV-19 or BBV152) was prospectively followed till discharge or death and matched [for age (±10 years), sex, baseline disease severity and comorbidities] with a retrospective group of unvaccinated patients admitted during the study period. Paired analysis was done to look for clinical outcomes between the two groups. Results: The study included a total of 210 patients, with 105 in each of the vaccinated and unvaccinated groups. In the vaccinated group, 47 (44.8%) and 58 (55.2%) patients had received ChAdOx1 nCoV-19 and BBV152, respectively. However, 73 patients had received one dose and 32 had received two doses of the vaccine. Disease severity was mild in 36.2%, moderate in 31.4% and severe in 32.4%. Two mortalities were reported out of 19 fully vaccinated individuals. All-cause mortality in the vaccinated group was 8.6% (9/105), which was significantly lower than the matched unvaccinated group mortality of 21.9% (23/105), p = 0.007. Vaccination increased the chances of survival (OR = 3.8, 95% CI: 1.42–10.18) compared to the unvaccinated group. Conclusion: In the second wave of the pandemic predominated by delta variant of SARS CoV-2, vaccination reduced all-cause mortality among hospitalized patients, although the results are only preliminary.


Introduction
Researchers across the globe have been constantly working to come out with effective vaccines to battle the pandemic of COVID-19. India began one of the world's largest vaccination campaigns against COVID-19 on 16 January 2021 with two approved vaccines, namely Covishield (ChAdOx1 nCoV-19) (by Serum Institute of India Ltd.) and Covaxin (BBV152) (by Bharat Biotech International Ltd.). Recently, heterologous recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V) and mRNA-1273 (Moderna) vaccine received emergency use approval in India. 1,2 By the beginning of July 2021, India had administered more than 335 million vaccine doses with 4.2% of the population being fully vaccinated according to the Ministry of Health and Family Welfare, Government Of India (MoHFW). 3 Reports of COVID-19 infections in vaccinated individuals are alarming and of urgent concern to add granularity to our understanding of the postvaccine immunology and further preventive strategies. During the inceptive phase of its vaccination drive, India was hit hard by the second wave of the COVID-19 pandemic with an exponential rise in cases during the middle of March 2021. 4 During this period, a study done at the Post Graduate Institute of Medical Education and Research, Chandigarh among healthcare workers reported 1.6% breakthrough infections in those vaccinated with ChAdOx1 nCoV-19. 5 Indian Council for Medical Research (ICMR) reported that post-vaccination breakthrough infections in India for ChAdOx1 nCoV-19 was 0.03% and BBV152 was 0.04%. 6 Similar studies have been reported from across the globe. 5,7 However, data after the end of this wave demonstrated that the breakthrough infection rate was much higher. About 13.1 8 -42.4% 9 of healthcare workers vaccinated with either one or two doses of ChAdOx1 nCoV-19 during the delta wave developed symptomatic COVID-19.
The most important vaccine efficacy endpoints are the severity of disease and mortality which are difficult to assess in phase III clinical trials. 10 Hence, there is a need for real-world vaccine effectiveness data with respect to preventing hospitalizations, disease severity and mortality. Currently, there is not much data available on the clinical profile of hospitalized COVID-19 patients who are vaccinated. In this study, we aim to understand the clinical profile and outcomes of admitted COVID-19 patients who had received at least one dose of either ChAdOx1 nCoV-19 or BBV152.

Methodology
This study was conducted in the dedicated COVID-19 healthcare facility of a tertiary care hospital in Northern India between March 2021 and June 2021. The main aim was to understand the clinical outcomes of vaccinated COVID-19 patients requiring hospitalization. The study was undertaken after approval by the Institute Ethics Committee (IECPG-337) with a protocol revision done in May 2021 to retrospectively include an unvaccinated control cohort. The study population included patients with confirmed SARS CoV-2 infection admitted to the COVID-19 centre, positive by nucleic acid amplification test or a rapid antigen test. We performed a 1:1 matched study between two groups of patients -the vaccinated COVID-19 group and the unvaccinated COVID-19 group of patients -to compare their clinical outcomes. Informed consent was taken from the study participants. Similarly, for the retrospective cohort, consent was taken via phone call, either from the patient or family members.

Group 1 -vaccinated COVID-19 patients
This group consisted of admitted COVID-19 patients who had received at least one dose of either ChAdOx1 nCoV-19 or BBV152 prior to hospitalization. After admission, they were classified to have mild (upper respiratory tract symptoms and fever without shortness of breath or hypoxia), moderate (respiratory rate ⩾ 24/min, or SpO 2 ⩽ 93% on room air) or severe disease (respiratory rate > 30/min, or SpO 2 < 90% on room air) as per institutional protocol. This group was prospectively followed up to discharge or death. Demographic details, clinical data (symptoms, admission vitals), baseline laboratory parameters (including inflammatory markers), the treatment received (highest oxygen delivery devices used, steroids, antivirals, anticoagulation) and clinical outcomes (all-cause mortality and duration of hospital stay) of patients were recorded in a pre-designed proforma.

Group 2 -unvaccinated COVID-19 patients (controls)
Details of all admitted COVID-19 patients at our facility during the study period were retrieved from electronic medical records. Vaccination status was re-verified telephonically. All confirmed COVID-19 patients who had not received any dose of SARS CoV-2 vaccine and were admitted during the same study period were recruited as the control group. This was the group with which all clinical outcomes of the vaccinated group were compared.

Paired matching
We performed a 1:1 matching between the two groups. The matching variables included age (±10 years), sex, the severity of disease at presentation and comorbidities. Wherever possible, exact comorbidities were matched; in the absence of exact matches, we tried to match the number of comorbidities and the best possible pair was taken including at least the major comorbidities (diabetes mellitus, hypertension, chronic kidney disease and coronary artery disease). Codes were generated for both groups based on the matching variables. An independent investigator blinded for all other variables except for matching variables performed the matching.

Results
This study included a total of 210 patients, with 105 in each of the vaccinated and unvaccinated groups who were matched 1:1 as per the criteria described earlier.
The median duration of hospital stay was 10 (7-14) days. All-cause mortality was 8.6% (9/105). Two deaths were noted in patients who had received two doses and completed 14 days postvaccination. Detailed mortality data have been presented in Supplementary Appendix- Table S2. Detailed demographic, clinical, baseline laboratory, treatment and clinical outcome data are presented in Tables 1-3.

Results of 1:1 matched analysis with unvaccinated COVID-19 patients
Matched analysis was performed to look for any difference in clinical outcome (all-cause mortality and duration of hospital stay) among vaccinated and unvaccinated groups. Age, sex, severity and major comorbidities were the matching variables. Among the laboratory parameters, median baseline C-reactive protein (16.7 mg/litre) was higher in the unvaccinated group but not statistically significant (p = 0.13). HFNC use was significantly higher in the vaccinated patients (16.2%, p = 0.008), while a significantly higher proportion of patients in the unvaccinated group required mechanical ventilation (21.9%, p = 0.003). Lowmolecular-weight heparin administration was significantly more (p = 0.04) in the unvaccinated group. There is a possibility of physician bias in the prescription, which cannot be ruled out. Among the clinical outcomes, all-cause mortality was significantly higher in the unvaccinated group 23/105 (21.9%, p = 0.007) compared to the 9/105 (8.6%) vaccinated group. The median duration of hospital stay was similar among the two groups (p = 0.84).

Subgroup analysis within the vaccinated patients -based on the type of vaccine and number of doses
Participants in both the vaccine groups (ChAdOx1 nCoV-19/BBV152) were similar in demographic profile, baseline severity, baseline laboratory parameters, baseline inflammatory markers and the treatment received except that the patients with coronary artery disease were more in the ChAdOx1 nCoV-19 group. There was no statistically significant difference in duration of hospital stay (p = 0.14) and all-cause mortality (p = 0.98) between the two vaccines.
All baseline data were similar between those who received one-dose vaccine and two-dose vaccines except that the number of patients with malignancy was higher in those who received two doses and median platelet count was lower in individuals who received one-dose vaccine than those who received two doses of vaccine. All-cause mortality (p = 0.57) and duration of hospital stay (p = 0.88) were not statistically different between one-dose and two-dose vaccine groups (Tables 1-3).

Discussion
The current efficacy data for various COVID-19 vaccines are calculated using the primary endpoint of preventing symptomatic illness. This varies from > 90% with the mRNA-based vaccines 11,12 to about 70% with the adenovirus-vectored vaccines such as ChAdOx1 nCoV-19. 13 Real-world data on vaccine effectiveness of BBV152 in a test-negative case-control study were 50%. 14 Arguably, the most important measure would be to know how effective the vaccines are in preventing moderateto-severe COVID-19 or death, especially in highrisk individuals. This is demonstrated in the fact that the focus of surveillance has now shifted to identifying and investigating only hospitalized or fatal cases of breakthrough infections. ICMR has also recommended all hospitals to provide systematic data on hospitalizations after vaccination.
Initial data during the delta wave from Eastern India reported that 9.9% (27/274) of patients with breakthrough infections required hospitalization. 15 Other studies which described breakthrough infections from India mainly reported either mild or asymptomatic infections, with healthcare workers as their major cohort. Among about 7000 healthcare workers in Vellore, vaccination with two doses of ChAdOx1 nCov-19 reduced hospitalization (Relative Risk = 0.23), need for oxygen therapy (Relative Risk = 0.08) and intensive care admission (Relative Risk = 0.06) significantly. 16 Prospective data from another cohort in Northern India   Severe disease and mortality were observed after complete vaccination. Comorbidities, such as diabetes mellitus, obesity, chronic lung disease including asthma, hypertension and chronic kidney disease, pose worse outcome in COVID- 19. This has been previously elucidated from multiple well-powered studies. [20][21][22] Of the few patients who developed extrapulmonary complications, we did note that NSTEMI and DVT occurred in those who had received ChAdOx1 nCov-19. This vaccine has been implicated in a few case reports to have led to myocardial infarction in the absence of COVID-19 infection as well. 23,24 Our study had few limitations. First, the severity profile and mortality may seem higher because the study was done at an apex COVID care facility which usually receives a high proportion of referred sick patients. However, the paired matching between vaccinated and unvaccinated patients takes care of this without affecting the outcome variable of mortality. Second, the data of our matched population were retrospective. All efforts were made to match the two groups for age, sex, comorbidities and baseline severity. However, we were unable to capture the data for severity progression among the unvaccinated group as it was retrospectively collected. There might be a possibility that the high allcause mortality in the unvaccinated group may have been due to reasons other than progression to severe disease. Third, given the rapid turnover of patients along with a paucity of manpower during this study period, several vaccinated patients could have likely been missed in our recruitment. We included the maximum number of vaccinated individuals we could. The resulting sample size was small. Moreover, the number of patients who were fully vaccinated (post two doses and post 14 days) was considerably less. This can be understood as the study was started in March 2021 coinciding with the second wave of COVID-19 which was close to the inception of the vaccination campaign in India from the middle of January. Finally, data on random blood sugar, antibody levels and genomic sequencing are lacking and would have provided additional conclusive information. However, we are aware that the predominant variant circulating during the study period was the delta variant.
This is one of the initial prospective studies to investigate the clinical details and outcomes among a hospitalized cohort of vaccinated patients. While more such studies can throw further light on outcomes in vaccinated individuals, until then we urge to follow infection prevention strategies and COVID appropriate behaviour along with the vaccine jabs.

Conclusion
The study coincided with the second wave of the COVID-19 pandemic which was predominated by the delta variant of SARS CoV-2. The vaccinated cohort had better outcomes for survival than the unvaccinated matched controls in the study. However, the higher all-cause mortality in the unvaccinated group may be due to reasons other than mere progression to severe COVID-19. This being a preliminary study requires further exploration into this aspect.

Declarations
Ethical approval and consent to participate Ethical clearance was obtained from Institute Ethics Committee, All India Institute of Medical TherapeuTic advances in vaccines and immunotherapy