key: cord-0939352-gzayg27m
authors: Tsundue, Tenzin; Namdon, Tenzin; Tsewang, Tenzin; Topgyal, Sonam; Dolma, Tashi; Lhadon, Dekyi; Choetso, Tsering; Woesal, Tenzin; Yangkyi, Tenzin; Gupta, Amita; Peters, David; Paster, Zorba; Phunkyi, Dawa; Sadutshang, Tsetan Dorji; Chaisson, Richard E; Dorjee, Kunchok
title: First and second doses of Covishield vaccine provided high level of protection against SARS-CoV-2 infection in highly transmissible settings: results from a prospective cohort of participants residing in congregate facilities in India
date: 2022-05-23
journal: BMJ Glob Health
DOI: 10.1136/bmjgh-2021-008271
sha: 86266e9151abc2c63db558a8433f8875806e6ec4
doc_id: 939352
cord_uid: gzayg27m

OBJECTIVES: This study aimed to determine the effectiveness of Covishield vaccine among residents of congregate residential facilities. DESIGN: A prospective cohort study in congregate residential facilities. SETTING: Dharamshala, Himachal Pradesh, India, from December 2020 to July 2021. PARTICIPANTS: Residents of all ages in seven facilities—three monasteries, two old age homes and two learning centres—were enrolled. EXPOSURES: First and second doses of Covishield vaccine against SARS-CoV-2 infection. MAIN OUTCOMES MEASURES: Primary outcome was development of COVID-19. Secondary outcome was unfavourable outcomes, defined as a composite of shortness of breath, hospitalisation or death. Vaccine effectiveness (%) was calculated as (1−HR)×100. RESULTS: There were 1114 residents (median age 31 years) participating in the study, 82% males. Twenty-eight per cent (n=308/1114) were unvaccinated, 50% (n=554/1114) had received one dose and 23% (n=252/1114) had received two doses of Covishield. The point prevalence of COVID-19 for the facilities ranged from 11% to 57%. Incidence rates (95% CI) of COVID-19 were 76 (63 to 90)/1000 person-months in the unvaccinated, 25 (18 to 35)/1000 person-months in recipients of one dose and 9 (4 to 19)/1000 person-months in recipients of two doses. The effectiveness of first and second doses of Covishield were 71% (adjusted HR (aHR) 0.29; 95% CI 0.18 to 0.46; p<0.001) and 80% (aHR 0.20; 95% CI 0.09 to 0.44; p<0.001), respectively, against SARS-CoV-2 infection and 86% (aHR 0.24; 95% CI 0.07 to 0.82; p=0.023) and 99% (aHR 0.01; 95% CI 0.002 to 0.10; p<0.001), respectively, against unfavourable outcome. The effectiveness was higher after 14 days of receiving the first and second doses, 93% and 98%, respectively. Risk of infection was higher in persons with chronic hepatitis B (aHR 1.78; p=0.034) and previous history of tuberculosis (aHR 1.62; p=0.047). CONCLUSION: Covishield was effective in preventing SARS-CoV-2 infection and reducing disease severity in highly transmissible settings during the second wave of the pandemic driven by the Delta variant.

Tenzin Tsundue, 1 Tenzin Namdon, 1 Tenzin Tsewang, 1 Sonam Topgyal, 1 Tashi Dolma, 2 Dekyi Lhadon, 1 Tsering Choetso, 1 Tenzin Woesal, 1 Tenzin Yangkyi, 1 Amita Gupta, 3, 4 David Peters , 3, 4 Zorba Paster, 5 Dawa Phunkyi, 1 Tsetan Dorji Sadutshang, 1 Richard E Chaisson, 6, 7 Kunchok Dorjee 4, 8 Original research 

Vaccines remain the primary tool to contain the COVID-19 pandemic. However, the recent surge of infection globally, the emergence of variants and the varying estimates of vaccine effectiveness based on vaccine type, geography and populations have cast doubts and confusion in the public. [1] [2] [3] [4] [5] [6] [7] Uptake is further challenged by resistance and hesitancy from sectors of society having unfavourable perceptions towards vaccines. [8] [9] [10] [11] As such, evidence of vaccine effectiveness in the real world in diverse settings and populations including local communities is needed.

India was gripped by a deadly second wave of the COVID-19 pandemic in 2021 as the vaccines were being rolled out. The government prioritised elderly and people with comorbidities to receive COVID-19 vaccines, and then it was made available for other adults. 12 13 This phased roll-out created a setting for natural experiment providing an opportunity to compare outcomes in people who were unvaccinated, who had received the first dose of vaccine and who had received two doses of vaccine. In this study, we determined the prevalence of COVID-19 and effectiveness of Covishield vaccine in congregate living facilities in the Tibetan community in Himachal Pradesh, India, that experienced outbreaks of COVID-19.

Delek Hospital is a community hospital and a designated COVID-19 testing and vaccine centre located in Dharamshala, Himachal Pradesh. The hospital attends to Tibetan and local Indian populations in the region and provides service to several residential facilities including monasteries, nunneries, boarding schools and old age homes. Residents interact in close-knit spaces in these institutes and transmission can happen rapidly. During the second wave in India, COVID-19 outbreaks happened in several living facilities in Dharamshala. Residents of all ages in three monasteries, two old age homes, one vocational centre and one language and culture learning centre where outbreaks happened were included in the study.

Ever since the start of the pandemic, Delek Hospital has been providing testing and prevention services to the boarding schools, monasteries, nunneries and other residential facilities in Dharamshala. Starting December 2020, the institutes have been actively monitored for outbreaks of COVID-19 using a surveillance system. COVID-19 task force at the Delek Hospital carried out regular follow-up of the residents of the congregate settings supported by healthcare workers of the respective institutes. A COVID-19 surveillance database was used to capture relevant data including vaccine administration and test results. Only Covishield (Oxford/Astra-Zeneca) vaccine was used. During outbreak in an institute, all residents were considered contacts and tested for COVID-19. Residents would receive COVID-19 tests either at Delek Hospital or at the residential facility itself carried out by the task force. Testing for SARS-CoV-2 was done using real-time reverse transcriptase PCR (RT-PCR) assays or rapid antigen test (RAT) on nasopharyngeal swabs. RT-PCR testing was carried out at a nearby Government Medical College Hospital. All persons detected with SARS-CoV-2 infection were quarantined at the institute itself or at a designated quarantine centre. Persons with severe COVID-19 or those identified as needing further care were referred to a tertiary care centre. The COVID-19 taskforce staff conducted interviews to obtain the sociodemographic and clinical information.

Receipt of vaccine against COVID-19 was the exposure variable. A resident was either unvaccinated, had received one dose or had received two doses of Covishield vaccine. A unique participant identifier was used to link subsequent vaccine administration and testing data to a participant.

Primary outcome was vaccine effectiveness, evaluated through the development of COVID-19 across the categories of exposure. A COVID-19 outcome was restricted to those episodes occurring after first or second dose of Covishield vaccine. Episodes of COVID-19 prior to the first dose of vaccine administration was classified as a 'previously exposed or past COVID-19' case. The study's secondary outcome, also referred to as 'unfavourable outcome' henceforth, was composite, consisting of shortness of breath (or use of supplemental oxygen), hospitalisation or death due to COVID-19.

Demographic and clinical history that were recorded included age, sex, occupation, place of residence, current smoking status, history of tuberculosis (TB), presence of chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD) (heart disease, stroke or hypertension), diabetes mellitus, chronic hepatitis B virus (HBV) and chronic kidney disease (CKD). For those testing positive for SARS-CoV-2 infection, information on symptoms-cough, fever, shortness of breath, loose stool, loss of smell, loss of taste-were collected. Given the relatively short study period, covariates were not timeupdated and the same values as that at the baseline were assumed over the course of the study. For example, age at baseline or presence or absence of a comorbidity at HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE AND/OR POLICY ⇒ Efforts must be made to simultaneously vaccinate all individuals residing in congregate residential facilities regardless of age, rather than a phased age-wise implementation. ⇒ Durability beyond 90 days must be investigated in future research that will inform the time for further booster doses.

baseline was assumed to remain so for the duration of the study. for COVID-19 before receipt of the first dose of Covishield vaccine were considered previously exposed. The secondary outcome, which was a composite outcome comprised of use of supplemental oxygen or shortness of breath, hospitalisation or death, was also assessed based on receipt of Covishield. Time scale for the participants was defined in terms of observed time-on-study in calendar months, with 20 February 2021 being the earliest start date of vaccine administration for the institutes. Participants started contributing exposure time after the receipt of the first dose of the vaccine. Vaccines were implemented for the institutes at different times, and hence, the start of follow-up period was different for the participants based on the time of vaccine implementation for the residential facility. Episodes of COVID-19 prior to receipt of vaccine were considered as 'previous COVID-19 ' and not included as an outcome. Participants were censored at the earlier of the first development of the outcome, or administratively on 31 July 2021. HRs were generated using Cox proportional hazard regression comparing the time to development of the outcome between the exposure categories. Effectiveness of the vaccine (%) is then calculated as (1−HR)×100. Because of the dependence of outcomes within the residential facilities, we used the Huber-White robust SE to account for clustering. Given that age and residence type may be correlated with the exposure variable, we checked for collinearity of the cofactors by calculating the variance inflation factor (vif) and tolerance (1/vif) post regression. Data were processed and analysed using STATA (Stata/BE V.17.0) software (StataCorp, College Station, Texas, USA).

Patients or members of the public are not involved in the design, or conduct, or reporting or dissemination plans of the research.

This study has been exempted by the Delek Hospital's Ethics Committee and the Johns Hopkins Medicine Institutional Review Board as an urgent public health initiative with the need for informed consent from individual participants waived.

Between December 2020 and July 2021, seven residential facilities in Dharamshala have experienced at least one outbreak (figure 1); two institutes have experienced two outbreaks. The point prevalence of COVID-19 during the outbreaks ranged from 11% to 57% in the individual facilities (figure 2A). The prevalence decreased with increasing age categories, which was in accordance with higher vaccination rates in older age residents (figure 2B). Most outbreaks (n=5) occurred in the month of May when India was facing the second wave of the pandemic. There occurred a total of 341 COVID-19 cases during the outbreaks. A total of 1145 COVID-19 Figure 1 Defining the cohort to determine effectiveness of Covishield vaccine against SARS-CoV-2 infection. *Unfavourable outcome defined as either death, hospitalisation or use of supplemental oxygen.

BMJ Global Health tests were carried out; 966 were RT-PCR-based tests and 179 were RAT.

Baseline characteristics Between 1 December 2020 and 31 January 2021, 1114 residents from seven residential facilities-two old age homes (n=183), three monasteries (n=636) and two learning centres (n=295)-were enrolled into the study (table 1) . Of the 1114 residents, 27.6% (n=308) were unvaccinated, 49.7% (n=554) had received only one dose of Covishield and 22.6% (n=252) had received two doses of Covishield vaccine (figure 1). Median age (IQR) of the residents was 31 (19-46) years; 12.4% (n=138) were children <15 years, 73% (n=817) were between 15 and 59 years and 14% were aged ≥60 years. None of the children were vaccinated, whereas 80% of residents between 15 and 60 years and 94% of residents above 60 years had received either one or two doses of Covishield vaccine. Majority (82%, n=914/1114) of the residents were males; this was because three of the seven facilities were monasteries. Greater proportion of females were vaccinated as compared with males (80.5% vs 70.6%; p=0.004). Of the comorbidities among residents, hypertension (10%) was most prevalent followed by chronic hepatitis B (5.9%), diabetes mellitus (3.2%), current smoking (2.9%), COPD (1.6%) and CVD (1.5%). History of TB was prevalent (11%). Compared with residents without comorbidities, those with comorbidities were more likely to be vaccinated (table 1) .

Of the 341 COVID-19 cases that occurred in the residential facilities during the outbreaks, 159 cases developed prospectively after start of vaccination. Incidence proportion of COVID-19 was 4.8% (n=39/807) in the vaccinated residents and 40% (n=120/308) in the unvaccinated residents. In bivariate analyses, residents who received Covishield vaccine had higher frequency of cough (46% vs 22%; p=0.003) and fever (41% vs 20%; p=0.009) as compared with those who did not. Frequency of shortness of breath was lower in vaccinated than unvaccinated residents (9% vs 18%; p=0.113). Of those who developed COVID-19, 51% (n=75) were asymptomatic. There was no significant difference in the cumulative incidence of As vaccination efforts were going on simultaneously as the outbreaks were happening, it was possible that participants might have been exposed 

to SARS-CoV-2 at the time of vaccination. Therefore, we carried out an additional analysis by restricting outcomes for all participants to 14 days after the date of first and second doses of vaccine. We found greater effectiveness of 93% and 98% after 14 days of first and second doses of Covishield vaccine, respectively (aHR (95% CI) for the first dose: 0.07 (0.03 to 0.15); p<0.001 and aHR (95% CI) for the second dose: 0.02 (0.002 to 0.15); p<0.001). On evaluation of protection against unfavourable outcomes after 14 days of vaccination, we found that one dose of Covishield was 86% effective (aHR 0.24; 95% CI 0.07 to 0.82; p=0.023) and two doses of Covishield was 99% effective (aHR 0.01; 95% CI 0.002 to 0.10; p<0.001). In a separate model, we assessed the relationship between time elapsed after the first dose of Covishield and SARS-CoV-2 infection. The variable for passage of time after the first dose was categorised as 14-29 days and 30-60 days. We observed no protection against infection for the interval of 14-30 days. However, the protection was marked between 30 and 60 days (aHR 0.01; 95% CI 0.002 to 0.10; p<0.001), showing vaccine effectiveness of 99% (95% CI 90% to 99.9%). There was insufficient power to assess effectiveness beyond 60 days. On conducting a sensitivity analysis by excluding residents with previous history of COVID-19, we did not observe meaningful difference in vaccine effectiveness against SARS-CoV-2 infection for first (HR 0.32; 95% CI 0.20 to 0.51; p<0.001) and second doses (HR 0.22; 95% CI 0.10 to 0.48 p<0.001) of Covishield. All the above models were adjusted for age, gender, residence type, history of TB, COPD, CVD (including hypertension), diabetes mellitus, chronic hepatitis B and current smoking history (table 3) . We did not encounter concerns of collinearity between variables included in regression model (mean vif: 1.26; range of tolerance of individual variables: 0.45 to 0.99).

In this study, we have demonstrated the real-world effectiveness of Covishield vaccine against SARS-CoV-2 infection and unfavourable outcomes using data from outbreaks in highly transmissible settings. We observed high point prevalence of COVID-19 ranging from 11% to 57% in the congregate living facilities during the second wave of the pandemic in India. The incidence rate of COVID-19 was ninefold higher in the unvaccinated as compared with the recipients of two doses of the vaccine (76/1000 person-months vs 9/1000 person-months) and of those who developed COVID-19, 51% had asymptomatic infection. Transmission was common in the younger age group which was evident from the lower median age of the infected persons, that is, 18 years, than the overall median age of all participants, which was 31 years. The first and second doses of Covishield were 71% and 86% effective, respectively, in protecting against SARS-CoV-2 infection in the first 3 months after vaccine administration. The effectiveness of the first and second doses of Covishield were higher, 93% and 98% respectively, after 14 days of administration. We found that two doses of Covishield reduces the risk of unfavourable clinical outcomes from COVID-19 including use of supplemental oxygen, hospitalisation or death by 98%.

Our findings largely conformed with that of other observational studies and clinical trials. In a large VIN-WIN cohort of ~1.5 million healthcare workers in India, vaccine effectiveness--after 2 weeks of vaccine administration-of 94% and 92% were observed for recipients of one and two doses of Covishield. 14 Although the results of the VIN-WIN cohort were not adjusted for potential confounders, the large sample of the study was valuable. In another large real-world study in England, vaccine effectiveness after 28-35 days of administration of first dose of ChAdOx1-S (Oxford-AstraZeneca, equivalent of Covishield) was 60%-73% for persons above 70 years of age. 15 Furthermore, a large prospective cohort study of ~1.3 million people in Scotland has shown that the first dose of ChAdOx1-S vaccine was 88% effective in protecting against hospitalisation between 28 and 35 days after administration. 16 In a pooled analysis of data from four randomised controlled trials in UK, Brazil and South Africa, effectiveness of ChAdOx1-S between 55% and 81% was observed depending on the duration of prime-boost interval with longer interval associated with greater effectiveness. 17 The higher effectiveness observed in this study may be attributable to the younger age of the participants in this study-86% were below 60 years with median age of 31 years. Additionally, a high baseline prevalence of past COVID-19 history in the vaccinated residents may have boosted the immunity.

We did not observe a protective effect against SARS-CoV-2 infection in the first 30 days of vaccination. This may be due to the following reasons: First, residents at the time of vaccination might already have been exposed to SARS-CoV-2. Vaccination drives were ongoing in India at the time of the study. Second, elderly persons and persons with comorbidities were selected to receive the vaccine first; prevalence of comorbidity and symptomatic COVID-19 were higher in them (table 1) . 18 This could imply a greater baseline susceptibility for the vaccinated group to spuriously drive down vaccine effectiveness toward null. Third, greater immunogenicity of Covishield vaccine has been documented after few weeks of vaccine administration. 17 19 Our finding of greater risk of infection and unfavourable outcomes associated with COPD is consistent with the existing literature. A lack of statistically significant association between cardiovascular disease and SARS-CoV-2 infection or unfavourable outcomes may be due to inadequate sample size as majority of participants in the study were of young age. We observed a statistically significant higher risk of SARS-CoV-2 infection in persons with previous history of TB. We are not aware of a prior study documenting this association but instead, studies BMJ Global Health 

in the past have suggested inverse relation between prior TB history or BCG vaccine and risk of COVID-19. 20 21 In the context of the conflicting findings, and a significant morbidity and mortality for coinfected patients, 22 the TB-COVID-19 relationship should be further investigated. Our finding of increased risk of SARS-CoV-2 infection for those with previous TB could be associated with a greater susceptibility secondary to post-TB lung damage.

An additional finding of this study has been that persons with chronic HBV infection were observed to have higher risk of SARS-CoV-2 infection. Most studies to date have described adverse clinical outcomes for persons with SARS-CoV-2 and chronic HBV coinfection. 18 23 However, it is unclear how infection with HBV influences the risk of SARS-CoV-2 infection; few studies have suggested a lower risk of infection for persons with chronic HBV infection prompting speculation on the possibility of 'immune exhaustion' as a result of long standing infection with HBV. 23 24 However, these studies were from the early phases of the pandemic in 2020. Given the constant evolution of the variants, further investigations to study the relationship between COVID-19 and chronic HBV are urgently needed. We did not calculate HR for events that occurred within 14 days of vaccine receipt because for one institute, there was an active outbreak of COVID-19 happening simultaneously as the vaccination was being administered. This meant that many of the residents might already be exposed and likely infected at the time of receiving the vaccine, but unaware of the infection status as the test results took time to come. It was likely that the knowledge and fear of the risk of exposure might have selectively driven the exposed participants to receive the vaccine. Therefore, for reasons based on temporal alignment and causal inference, calculating the hazard for participants for this specific interval could result in biased estimates of the true effect of vaccine. Barring this one institute, none of the institutes had recorded COVID-19 in the first 14 days of vaccine administration. We have arbitrarily decided to use '14 days' as the cut-off because vaccine administration would usually be complete for all the residents by that time.

A key strength of the study is its prospective and population-based nature where all residents of the institutes were assessed for exposure and outcome that could ensure a stronger causal inference. The study population included all age groups giving it generalisability, especially for those aged 15-59 years old that constituted majority of the participants. An additional strength has been the characterisation of COVID-19 outbreak in residents of congregate facilities that could be reflect the situation in many other settings where people live together in close-knit spaces. This is the first study to document the COVID-19 status and vaccine effectiveness in congregate facilities of Tibetan refugees in India, a highly vulnerable population group.

While we could not type the SARS-CoV-2 strains, the outbreaks happened during the second wave of the pandemic in India that was largely driven by the Delta variant (B.1.617.2). Therefore, it may be reasonable to associate the findings from this study to that caused by the Delta variant of SARS-CoV-2. A limitation could be the relatively smaller sample that prevented us from assessing the outcome of hospitalisation or death separately, and limited follow-up time precluding calculation of vaccine effectiveness beyond 60 days.

We conclude that the first and second doses of Covishield vaccine were highly effective in preventing SARS-CoV-2 infection in highly transmissible settings, mitigating disease severity and preventing death. With accrued person-time, we expect to describe the effectiveness stratified by age, prime-boost and post-boost time intervals with greater confidence.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Data availability statement Data are available upon reasonable request. As the data are generated from communities of Tibetan refugees in India, they are sensitive. We will make the data available on reasonable request.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Author note The reflexivity statement for this paper is linked as an online supplemental file 1.

David Peters http://orcid.org/0000-0001-8377-3444

Effectiveness of mRNA Covid-19 vaccine among U.S. health care personnel

Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months

Effect of delta variant on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK

Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial

Comparative Effectiveness of Moderna

Effectiveness of an inactivated SARS-CoV-2 vaccine in Chile

Effect of 2 inactivated SARS-CoV-2 vaccines on symptomatic COVID-19 infection in adults: a randomized clinical trial

COVID-19 vaccine hesitancy and resistance: correlates in a nationally representative longitudinal survey of the Australian population

A global survey of potential acceptance of a COVID-19 vaccine

Estimates of vaccine hesitancy for COVID-19 Atlanta

Understanding COVID-19 vaccine hesitancy

Strategy for COVID-19 vaccination in India: the country with the second highest population and number of cases

All above 60 years of age, 45-plus with comorbidities can get COVID-19 vaccine from March 1

COVISHIELD (AZD1222) vaccine effectiveness among healthcare and frontline workers of Indian armed forces: interim results of VIN-WIN cohort study

Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study

Interim findings from firstdose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study

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

Prevalence and predictors of death and severe disease in patients hospitalized due to COVID-19: a comprehensive systematic review and meta-analysis of 77 studies and 38,000 patients

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)

Relationship of prior pulmonary tuberculosis with the occurrence of Covid-19 pneumonia: review of 500 plus HRCT chest scans from two different centres of Sindh, Pakistan

Association of the past epidemic of Mycobacterium tuberculosis with mortality and incidence of COVID-19

Tuberculosis and COVID-19 co-infection: description of the global cohort

Association between chronic hepatitis B infection and COVID-19 outcomes: a Korean nationwide cohort study

Inverse association between chronic hepatitis B infection and coronavirus disease 2019 (COVID-19): immune exhaustion or coincidence?

Author affiliations 1 Acknowledgements The authors are thankful to the support from community members, health staff, leaders of the institutions and district health officials who have supported the vaccination campaign.Contributors KD: Conceptualisation, study design, funding acquisition, investigation, data curation, formal analysis, methodology, project administration, resources, supervision, writing-original draft, writing-review and editing, and guarantor of overall content. T Tsundue: Investigation, study design, methodology, supervision, project administration, data analysis, writing-original draft, writingreview and editing. TN: Investigation, methodology, writing-review and editing. Tenzin Tsewang: Investigation, writing-review and editing. ST: Investigation, supervision, writing-review and editing. TD: Investigation, writing-review and editing. DL: Investigation, resources, supervision, writing-review and editing. TC: Investigation, resources, supervision, writing-review and editing. TW: Investigation, writing-review and editing. TY: Data curation, investigation, supervision, writing-review and editing. TK: Investigation, writing-review and editing. AG: Investigation, resources, validation, writing-review and editing. DP: Investigation, resources, validation, writing-review and editing. ZP: Funding acquisition, investigation, resources, supervision, writing-review and editing. DP: Funding acquisition, investigation, project administration, resources, supervision. TDS: Investigation, methodology, resources, supervision, writing-review and editing. REC: Funding acquisition, investigation, project administration, resources, supervision, validation, writing-review and editing. 

Competing interests None declared.