Right from the onset of the Covid-19 pandemic, it was evident that some groups are more vulnerable to serious disease—males; those above the age of 65; those having hypertension, diabetes, obesity, chronic underlying renal, cardiac, hepatic or pulmonary disease; those on immunosuppressants; and those on chemotherapy for malignant disease.
It is easy to understand how those with chronic illnesses, organ dysfunction, immunosuppression or malignancy have poor immune responses. This has been shown with other viral infections—Hepatitis B for example. The reasons for the predilection of males, obese subjects and those in the older age group to serious coronavirus infection are not very clear. The virus can cause serious disease even if the inoculum is small, if the immune system of these subgroups is in some way unable to mount an adequate immune response. Do we have evidence that there is an inadequate immune response in men, obese subjects and senior citizens?
A study on fully vaccinated healthcare workers published in The Lancet throws some light on this important question. They studied the antibody titres against the virus in a large number of fully vaccinated healthcare workers using a standardised automated chemiluminescence assay; they found that the antibody response is significantly lower in precisely those individuals—the older age group, men, those who are obese—who develop severe disease with natural infection. What are the practical implications of these important observations for vaccination against Covid?
Those in the older age group, particularly men if they are also obese, will not develop good antibody titres against the virus. It is a common observation during the second wave in India that even subjects who have completed two doses of vaccine are getting infected and that some of them become seriously ill. Men over the age of 65 and obese individuals with a Body Mass Index of more than 30 constitute a significant proportion of India’s population and therefore, the suboptimal immune response in them to vaccination is of public health importance.
In India now, two vaccines are in use: Covishield and Covaxin. The most common vaccine used in India so far is Covishield. It is prepared using a Trojan horse approach—complementary DNA coding for the spike protein, derived from coronavirus RNA, is inserted into a non-replicating chimpanzee adenovirus to prepare the vaccine. Covaxin is an inactivated whole virus vaccine. Both are administered as two doses; Covishield 12 weeks apart and Covaxine 4-6 weeks apart.
Covishield was originally intended to be a single dose vaccine but a second dose was added on as the antibody response to a single dose was not adequate. The problem is that the human immune response is directed not only against the virus-derived spike protein but also against the adenovirus vector. Therefore, a third dose of a vectored vaccine is unlikely to elicit the required degree of immune response and antibody titre because antibodies against the vector virus will inactivate the virus before it can act to produce a booster response. If an inactivated vaccine is used after two doses of a vectored virus vaccine, it is possible that the protective efficacy in these vulnerable subjects may be enhanced. Inactivated vaccines are designed to evoke a broad range of immune responses against several viral antigens, not just the spike protein. Further, we know that mRNA vaccines that elicit a vigorous immune response and high antibody titres are effective against the variants of concern, including the delta virus. A boosted antibody response to a third dose of the vaccine may be expected to work in a similar fashion and be effective against variants of concern.
Taken together, these observations imply that older individuals, particularly men and those with obesity, may need a third dose of the vaccine as a booster in order to achieve adequate levels of protective antibodies. For those who had two doses of a vectored vaccine, the third dose can be an inactivated virus vaccine. For those who had received two doses of an inactivated virus vaccine, a third dose with the same inactivated vaccine may serve as a booster.
There is an urgent need to study post-vaccination neutralising antibody (nAB) titres against all known variants of concern in men and women over 65, those who are obese (BMI>30) and those with comorbidity. This will give a clearer picture of the effects of biological variables such as age, gender, BMI and other comorbid conditions on vaccine-induced immunity. If nAB titres are low in these subgroups after the standard two-dose regimen, a further study to evaluate the impact of a third dose is necessary.
It is important that such studies are carried out quickly in order to plan the vaccination strategy for special sub-groups with a poor antibody response to vaccination. The National Institute of Virology has the capability to measure nAB; the Indian Council of Medical Research will do well to quickly initiate a research study to clarify these issues.
While awaiting these study results, elderly men and women, those who are obese and those with comorbidity, even if fully vaccinated, should continue to be rigorous in their adoption of Covid-appropriate behavior in order to escape infection.
Dr M S Seshadri, Medical Director, Thirumalai Mission Hospital, Ranipet
Dr T Jacob John, Former professor of Clinical Virology, CMC, Vellore