Learning from Covid-19 vaccination experience
The Covid-19 vaccination experience has opened a plethora of possibilities for adult vaccination
A recent scientific article titled “Factors associated with sudden deaths among adults aged 18-45 years in India”, based on a multicentric matched case-control study led by the Indian Council of Medical Research (ICMR) scientists and published in the Indian Journal of Medical Research (IJMR), has triggered a lot of interest. This study examined the media reports of a spate of unexplained deaths in young adults seemingly linked to the after-effects of Covid-19 vaccination. The study did not find evidence to link the risk of unexplained sudden death among young adults with Covid-19 vaccination. It concluded that a history of past Covid-19 hospitalisation, a family history of sudden death and certain risky behaviours were possible explanations.

The study was led by some of the finest epidemiologists in the country and analysed data from 47 tertiary care hospitals, ensuring geographic representation.
There is a consensus that Covid-19 vaccines have been successful in preventing all-cause mortality across age groups and settings. Excess deaths on account of cardiovascular causes and stroke have been linked to SARS-CoV-2 infection: Estimates of the quantum of such deaths have been the matter of some debate though. The global incidence of sudden unexpected deaths is 0.8-6.2 per 100,000 per year and the common causes are cardiovascular — arrhythmia, myocardial ischemia, cardiomyopathy, myocarditis, aortic aneurysm, and valvular diseases. Sudden death, or sudden unexplained death, can be “witnessed” (observed by someone) or “unwitnessed”. In this case, the research question is centred around whether such deaths were linked to Covid-19 vaccines.
To examine this question, the study adopted a case-control design, appropriate for investigating rare conditions such as this. Some participants have the outcome of interest (referred to as cases), while others do not have the outcome (referred to as controls). Cases are defined as specifically as possible.
Epidemiologists make a distinction between “association” and “causation”. Association of a presumed cause with its presumed effect is a statistical reasoning based on the presence and strength of probabilities, factoring in so-called chance occurrence.
An absence of association refutes causality. Causation means either the production of an effect or the relation of cause to effect. Confounding is a distortion and occurs when the primary exposure of interest is mixed up with some other factor/s that is/are associated with the outcome. The extraneous factor must be associated with both the primary exposure of interest and the outcome of interest. For example, age can be a confounding factor if the inquiry is to ascertain the strength of the association between physical inactivity and heart disease as it is associated with exposure (older people are more likely to be inactive), and it is also associated with the outcome (older people are at greater risk of developing heart disease). Subjects who are physically active may drink more fluids (water and sports drinks) than inactive people, but drinking more fluid has no effect on the risk of heart disease, so fluid intake is not a confounding factor here.
This study drew upon cases who were aged 18-45 years and experienced sudden unexpected death, including sudden cardiac death, and were registered in the study hospitals between October 1, 2021, and March 31, 2023. From an initial list of 29,171 potential cases, 729 cases and 2916 matched controls (for every case there were four controls) were studied. The proportion of unvaccinated was 31.6% among cases and 23.6% among controls. The odds were highly statistically significant for these key variables: Hospitalisation for Covid-19, family history of sudden death, currently a smoker, and vigorous intensity of physical activity performed 48 hours before death/interview.
Globally, serious adverse events reported with the Covid-19 vaccines have been rare. There were reports of risk of myocarditis and myopericarditis (and consequent deaths) associated with mRNA vaccines including BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna).
Increased risk of thrombotic and other rare cardiovascular events after the ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca, Covishield in India) were reported. A robust study in the UK to investigate the risk of cardiac and all-cause mortality in the 12-29 years age group found no such significant increase in the 12 weeks following Covid-19 vaccination compared to more than 12 weeks after any dose.
It observed an increase in cardiac deaths in women after the first dose of non-mRNA vaccines (these vaccines have not been used in India). It also noted that a positive SARS-CoV-2 test was associated with increased cardiac and all-cause mortality among both vaccinated and unvaccinated persons at the time of testing; this study made a similar observation too. The balance of the argument in the public health literature has relied on the absolute risk of severe complications being low against the increased risks associated with SARS-CoV-2 infection if unvaccinated.
The Covid-19 vaccination experience has opened a plethora of possibilities for adult vaccination. Adult vaccination with the BCG vaccine (currently administered to neonates) may be considered with an aim towards the TB elimination goal and the ICMR is conducting a trial.
Traditional vaccine development from discovery and design required 15 years or longer and pre-clinical testing another 5-10 years. The unprecedented response time in the case of Covid-19 vaccines was enabled by the efficient deployment of adaptive clinical trial designs. While that has been a defining moment for science, vaccinology and immunisation programmes, the critical need for a climate of transparency and data sharing for scrutiny and debate cannot be overemphasised.
Rajib Dasgupta is professor (community health), Jawaharlal Nehru University, and editor, Indian Journal of Public Health. The views expressed are personal
