Protection offered by COVID-19 vaccines in reducing SARS-CoV-2 infection frequency; severity and mortality, among Indian Healthcare Workers: Multicenter, pan-Fortis study

During COVID-19 pandemic, Healthcare Workers (HCWs) were at increased risk for exposure to SARS-CoV-2 virus and prioritized for early administration of COVID-19 vaccines in India. Real-life scenario information among vaccinated HCWs acquiring COVID-19 infection, is scarce. We retrospectively analyzed COVID-19 infection frequency, severity, and associated mortality among healthcare workers, immunized with either Covishield or Covaxin vaccines at 27 Fortis Hospitals across 11 Indian states. Positive cases were identied based on RT-PCR or rapid antigen tests for SARS-CoV-2 between 16th January 2021 till 15th May 2021. 20034 HCWs received vaccination. 3971 received 1 dose, 16063 received 2 doses. Post-vaccination, 1139 HCWs acquired COVID-19 infection, 180 (4.53%) and 959 (5.97%) among partially and fully vaccinated category, respectively. Breakthrough infection occurred among 913 (5.68%) HCWs. Concurrently, Case Positivity Rate was 11.9%, among general population (control). Among 1139 positive cases, mild, moderate, and severe infections were 1059 (93%), 71 (6.2%) and 9 (0.8%), respectively with Case Fatality Rate of 0.18%, compared to 0.92% among general population (p=0.0043). The Case Fatality Rate in vaccinated HCWs was found to be 80% less than that in general population (control). Hence, COVID-19 vaccines available in India seem to be effective against SARS-CoV-2 virus. and Covaxin Biotech’s BBV152 . The former is a replication-decient simian adenoviral vector containing full length codon-optimized coding sequence of SARS-CoV-2 spike protein along with a tissue plasminogen activator (tPA) leader sequence. The pooled analysis of 4 randomized trials of the AstraZeneca-Oxford University vaccine reported an overall ecacy of 66.7% (95%CI 57.4%-74%) after 14 days of a two-dose vaccine given at 4-12 weeks interval 4 . Covaxin is an inactivated virus based COVID-19 vaccine, which was developed by treating the virus from Vero cell cultures by beta-propiolactone which deactivate the virus gene while keeping the other viral particle intact. The ecacy of 2 doses of Covaxin at 4-week interval have been claimed to be 78%, based on interim trial result analysis released to press by Bharat Biotech 5


Introduction
The ongoing COVID-19 pandemic has infected >232 million people globally and >33 million in India since its origin in December 2019 1 . The pandemic is associated with considerable disease mortality, morbidity and economic loss resulting from various control measures needed to limit spread of virus and community transmission. Rapid development of vaccines against the said virus was achieved and For licensing purposes vaccine e cacy trials need Randomized Control Trial (RCT) data with adequate sample. Such RCTs importantly evaluate three relevant aspects of a vaccine e cacy viz: reduction in infection (sterilizing immunity); reduction in severity of infection (disease modifying immunity); reduction in duration of infection (infection clearing immunity). Such results represent the best-case scenario for assessing vaccine e cacy & licensing. But vaccine e cacy always does not predict vaccine effectiveness i.e., protection attributed to vaccine administered non-randomly under eld conditions. Further, vaccine effectiveness in real life, is not re ected by RCTs restricted to a particular age group, ethnicity, or geographical area. For this reason, studies are needed to assess vaccine effectiveness in reallife scenario after the licensing. Further, the reliability of vaccine effectiveness in real-life scenarios, may be augmented by its evaluation in a cohort of high-risk population who are most likely to contract COVID-19 infection, such as active HCWs working during pandemic 6,7 . In such population, the e cacy of a vaccine can be assessed by the frequency of COVID-19 infections detected by RT-PCR and rapid antigen tests on naso-pharyngeal swabs, severity of infection by assessing the number of immunized requiring hospitalization/ oxygen inhalation/ assisted ventilation and resultant mortality rate.
On 16th January 2021, Fortis vaccination program commenced for immunization of HCWs at network hospitals across India. Since February 2021, the 2nd wave of COVID-19 pandemic is active in India, with peak positivity rate (proportion of positive tests to total samples tested), hospitalization rate, ICU admissions and mortalities recorded between 15th April 2021 and 15th June 2021 8 . Therefore, a comparison of positivity rate, severity of COVID-19 disease manifestation and mortalities among the vaccinated HCWs and general population (control), may assess the effectiveness of the vaccination strategy adopted by India. Present study describes the COVID-19 infection dynamics among the vaccinated HCWs working at 27 Fortis Hospitals across 11 states in India and the study period included the duration of maximal assault of COVID-19 infection in India.

Study Design & Participants
It is a retrospective analysis of COVID-19 vaccinated cohort comprising of healthcare workers employed at Fortis Hospitals across 11 states in India. The study period is from 16 th January 2021 till 15 th May 2021. All healthcare workers who received at least one dose of the vaccine were included in the analysis.
The interval between 1 st dose and the 2 nd dose of COVID-19 vaccine was between 4 to 12 weeks as per prevailing government guidelines. The healthcare workers included in the study comprised of doctors, who were actively treating patients (covid and non-covid), nurses, paramedics, support staff including housekeeping, security, food & beverage, and administrators regularly coming to hospitals. All participating 27 Fortis Hospitals were providing care services for both Covid as well as non-Covid patients. All healthcare workers included in the study followed covid appropriate behavior, in and outside the hospital. All vaccinated healthcare workers included in the study were neither subjected to RT-PCR/ rapid antigen testing on respiratory specimen nor covid antibody assessment before vaccination. Symptomatic healthcare workers who underwent RT-PCR/ rapid antigen testing post-vaccination and found to be positive, were diagnosed to have COVID-19 infection. For the vaccinated healthcare workers acquiring COVID-19 infection, demographic data and details related to their hospital admission, oxygen requirement, assisted ventilation and morality were retrieved from the Fortis Hospital data base, maintained for vaccination purpose. Details on COVID-19 disease manifestation, and mortalities among the general population (control) were collected for comparison. In relation to the study period, the vaccine frequency of two doses of the licensed vaccine amongst Indian population did not exceed 3% 8 . (Total share =10.13%; share of people fully vaccinated =2.9%; share of people partially vaccinated =7.2%). Thus, nearly 97% of the general population in India were nonvaccinated during study period and served as the control population in the present study.

Data Source and Management
Each hospital made use of a standardized questionnaire and clinical record format to maintain employee demographic data and vaccine related information. While corresponding information for control population was sought from reliable online sources 9,10 . Information on severity of symptoms among personnel and mortality after one and both doses of vaccine were obtained separately from hospital records. The event day or date of COVID-19 positive test report (RT-PCR/ rapid antigen testing) was retrieved to assess the total covid positivity frequencies as well as breakthrough infection among the vaccinee cohorts.

Study Variables
Covid-19 positive cases were identi ed as those detected with SARS-CoV-2 RNA or antigen in a respiratory specimen on RT-PCR or rapid antigen testing. Breakthrough infections were cases with detection of SARS-CoV-2 RNA or antigen in a respiratory specimen collected from a person ≥14 days after they have completed all recommended doses of COVID-19 vaccine 11 . Classi cation of mild, moderate, and severe covid infection was de ned by following criteria 12 :

Mild infection
Upper respiratory tract symptoms like cough, sore throat &/or fever without shortness of breath or hypoxia (SpO 2 >94% after 6-minute walk).
Any oxygen inhalation to maintain SpO 2 above 94% was considered as oxygen requirement in hospitalized healthcare workers.
Assisted ventilation refers to an individual needing CPAP, BiPAP or intubation using a mechanical respirator.
Follow-up: The Covid-19 vaccination program was instituted from 16 th January 2021, at all 27 Fortis hospitals included in this study. The cutoff date (for censuring data) was 15 th May 2021. All healthcare workers, who received the Covid vaccine and whose data was retrievable were included in the study.

OUTCOME MEASURES
Primary outcome measures: To assess COVID-19 mortality rate among vaccinated HCWs in comparison to the general population (control) during the COVID-19 pandemic.
Secondary outcome measures: To assess COVID-19 infection frequency among vaccinated HCWs and evaluate the severity of disease in the said group.
Statistics analysis: Categorical variable are expressed as number (percentage) and comparison between groups was performed with Chi-square test (Fisher's exact test), as applicable. Continuous variables are expressed as Mean ± Standard Deviation. A p-value <0.05 was considered statistically signi cant. All statistical analyses were performed using the SPSS software (SPSS Version 25).

Results
The 27 sites included in the study (Table 1) had 26040 personnel of whom 20034 were administered vaccines, either the scheduled two doses of vaccine (n=16063: 80.2%) or one dose (n=3971: 19.8%). The remaining 6006 employees were migratory/ contract personnel whose vaccination data was not available and were therefore excluded from the study. Table 1. enlists the hospitals, distribution of healthcare workers, and the frequency of vaccine doses administered to them. Doctors, Nurses, Paramedics (including support staff) and Administrators constituted 18% (n=4696), 26% (n=6769), 47% (n=12239) and 9% (n=2336) of HCWs, respectively. Ninety percent of the HCWs included in the study received Covishield vaccine (AstraZeneca's ChAdOx1 nCoV-19 vaccine (AZD1222) and remaining 10% of the vaccinated HCW cohort received Covaxin (Bharat Biotech's BBV152 COVID-19 vaccine During the study period, a total of 1139 (5.68%) of the 20034 vaccinated HCWs were reported to be positive for SARS-CoV-2 (RT-PCR or rapid antigen testing on nasopharyngeal swab). After one dose of vaccination (n=3971), 180 (4.53%) ( Table 2) had COVID-19 infection before they received the second dose and after both the doses (n=16063), 959 (5.97%) ( Table 2) had infection. Breakthrough infection (≥14 days after both doses of vaccination) was documented in 913 (5.68%) ( Table 2) of the vaccinated cohort, indicating that 46 of the fully vaccinated group had COVID-19 infection after the second dose but within 14 days of the last dose of vaccination.
As explained in Table 3, the mean age for Doctors/ Nurses/ Paramedics (technicians/ housekeeping/ security)/ Administrators was found to be 43/ 31/ 36/ 37 years respectively.
During the same study period the COVID-19 case positivity rate among the general population in 11 states (n=79,13,53,000) where the 27 Fortis hospitals exist was found to be around 11.92% (Table 4).
Apparently, the infection rate amongst the vaccinated HCWs seemed markedly lower. We did not statistically compare the above two groups, because the population infection data indicated case positivity rate (number of positive tests/total number of tests done), whereas being a retrospective analysis the present study did not calculate case positivity rate among the vaccinated HCWs but, included those who were symptomatic and got tested. The total vaccinated cohort were not tested prospectively for COVID -19, thereby the actual case positivity rate was not available for them. Despite this lacuna, it seems that vaccinated HCWs had lower rate of infection. Among the infected HCWs (N=1139), the proportion of Doctors, Nurses, Paramedics and Administrators were 23% (n=262), 43.4% (n=495), 15.7% (n=179) and 17.8% (n=203) respectively. When the proportion of infected HCWs were assessed among the total staff under each category, it was seen that the frequencies of infection among doctors, nurses and paramedics were 5.5% (262/4696), 7.3% (495/6769), and 1.5% (179/12239). This would indicate that post vaccination, COVID-19 infection may be higher among the nurses as compared to doctors and other paramedics.
Among the vaccinated COVID-19 infected HCWs (N=1139), 93% (n=1059), 6.2% (n=71), and 0.8% (n=9) had mild, moderate (only oxygen required through nasal prong/ mask) and severe (ICU admission, assisted ventilation) COVID-19 infection respectively (Table 8). Two patients died (0.18%). One patient died after one dose of the vaccination and the other died after 14 days of receiving both doses of vaccination. Because more than 90% were mild infection the distribution of the degree of severity was not markedly different across the age/gender or categories of the staffs. During the same study period the case fatality rate among all the COVID-19 positive cases (n=94,31,527) in the control population (infected population in the 11 states where Fortis hospitals exist), was 0.92% (n=86,627) ( Table 9). The mortality rate among the vaccinated and infected HCWs was found to be 80% lower than the control population (0.18% vs 0.92%; p= 0.0043; sher's exact test) which is a signi cant nding.
The mean time interval, between last vaccine dose and positive test report was 47 days, 50 days, and 52 days for partially vaccinated, fully vaccinated and breakthrough cases, respectively (Table 10).

Discussion
The present study provides the dynamics of COVID-19 infection among vaccinated HCWs in tertiary care settings across 27 Fortis hospitals in India. Despite being a retrospective, descriptive analysis, the study reveals three important aspects of COVID-19 vaccine in a group of immunized, high-risk individuals (HCWs), namely: 1. It seems, COVID-19 infection rate amongst vaccinated HCWs was markedly lower as compared to control population. 2. Disease manifestation amongst the vaccinated HCWs was found to be largely mild in 93% cases; with moderate symptoms in 6% cases while severe symptoms were manifested in just 0.8% cases, needing ICU care/ assisted ventilation. 3. The case fatality rate amongst the high-risk group of HCWs was found to be 80% lower as compared to control population. The present study did not analyze or compare the two vaccine groups with each other since proportion of Covishield administered doses was ~90% and heavily skewed in favor of one group. Therefore, any comparison seemed redundant.
The above-mentioned vaccines are reported to have a protective e cacy of 67 to 78%. The present study documented a signi cantly lower rate of infection amongst the vaccinated HCWs who were actively working during the pandemic, at a time when the infection frequencies were reported to be amongst the highest. As mentioned in result section, an infection rate varying between 4.5-5.97% among the vaccinated HCWs was markedly lower than the case positivity rate of ~12% during the same period, observed in the control population of 11 Indian states where Fortis hospitals exist ( Table 2, 4). However, as described in result section, the COVID-19 infection rate amongst HCWs reported in the present study were not case positivity rate because the number of total vaccinated HCWs were not tested for presence of COVID-19 infection prospectively and the reported frequencies among this group was derived from overtly symptomatic HCWs who were tested. Despite this short coming the markedly lower rate of COVID infection among the vaccinated cohort of HCWs may not be ignored and provides an important observation.
Amongst the infected cohort of vaccinated HCWs, the clinical manifestation was mild in >90% cases. Severe clinical manifestation indicated by ICU care/ assisted ventilation was less than 1% and only 0.18% among the infected cohort of HCWs died due to the disease. During the study period the infected control population (population in the 11 states where Fortis hospitals exist) had a mortality rate of 0.92% which was signi cantly higher than the mortality rate of 0.18% amongst HCWs (p=0.0043) ( Table 9), thereby indicating a reduction of mortality rate by nearly 80% after vaccination. Indeed, ICMR (Indian Council of Medical Research) reported that 2 doses of COVID-19 vaccine prevented death by nearly 98% 13,14 . However, reduction in mortality rates among high-risk groups post-vaccination, assessed during peak of pandemic, using locally available vaccines has not been reported earlier. Therefore, the present results would assure the medical fraternity all over the country about the bene ts of COVID-19 vaccines that are locally available in India. The above-mentioned bene t was observed across all categories of Fortis employees.
A recent publication evaluated effectiveness of COVID-19 m-RNA Vaccine BNT162b2 vaccine (P zer-BioNTech) and mRNA-1273 vaccine (Moderna) 15 . The study was conducted across 25 U.S. states, representing more than 500,000 health care personnel. Vaccine effectiveness was evaluated by subjecting immunized healthcare personnel to RT-PCR or rapid antigen testing for SARS-CoV-2.
Participants who tested positive for SARS-CoV-2 were identi ed as cases (n=1482) while those who tested negative were identi ed as controls. After complete vaccination, vaccine effectiveness was 88.8% (95% CI, 84.6 to 91.8) and 96.3% (95% CI, 91.3 to 98.4), respectively. Vaccine protection was documented across all age groups and even those with comorbidities. However, the study did not evaluate any possible reduction in mortality rate.
The present study has several lacunae. It, being a retrospective study, could not assess true case positivity rate among the vaccinated HCW cohort, because the vaccinated HCWs were neither tested for COVID-19 infection before vaccination nor were they tested after vaccination. Those who had symptoms and tested positive for COVID-19 were the ones available for further analysis. The study could not compare the severity of clinical manifestation among the HCWs and control population due to nonavailability of severity data among the infected control population. The information on comorbidity among the vaccinated cohort was not available and therefore in uence of comorbidities on COVID-19 infection after vaccination could not be ascertained. Since >90% vaccinated cohort had mild infection, the in uence of advanced age and other known factors associated with severity of illness could not be studied. Importantly, the adoption of COVID-19 precautionary measures by HCWs, such as, use of Personal Protective Equipment (PPE) and access to repeated sanitization/ disinfection safety measures, could have been instrumental in increasing overall vaccine effectiveness and safety.
However, the strength of the study was evaluation of vaccine effectiveness in a real-life scenario at 27 sites across 11 Indian states, amongst high-risk group of individuals being continuously exposed to COVID-19 infection.
In conclusion, the study demonstrates that the COVID-19 vaccine, locally available in India, could offer substantial bene ts to high-risk individuals such as Healthcare Workers by reducing frequency of infections, lowering severity of illness, and signi cantly reducing mortality rate once infected.

Declarations
Acknowledgments: Source of support is Fortis Healthcare Limited