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The scientific enquiry on Covid-19 immunity – analysis


In eight months since the onset of Covid-19, over 47,000 scientific papers dealing with the disease have appeared in journals. This translates into about 5,875 papers per month. It took 20 years to have the same number of publications on the discovery of the human genome. This rate of scientific enquiry is unprecedented. More than half the publications deal with the key features of innate (pre-existing, ready to attack) and adaptive (more potent and desired) arms of the immune response, and towards ascertaining the long-term B- and T-lymphocyte immunological memory against the Sars-CoV-2 virus. The data generated has been helpful in forecasting the outcome of the disease, and developing effective strategies to control it. Five takeaways from these immunology-focused studies deserve mention.

First, on the antibody response. The initial burst of immunoglobulin M (IgM) and immunoglobulin A (IgA) response that appears around day seven of the onset of symptoms starts to decline from week four onwards, reaching near zero levels soon after. The much-needed immunoglobulin G (IgG), which also acts as the virus neutralisation antibody, starts to appear by day 10, reaching a peak between weeks five and eight and then slowly goes on the decline, three months onwards. The short-lived antibody response, however, is no cause for concern. Antibody responses almost always decline following the initial phase of infection because most of the B-cells that secrete them or their precursors (called plasma cells) are short-lived. Yet, there is a small-but-effective pool of long-lived B-cells that maintain immunological memory to the same pathogen. These are enough to produce highly potent neutralising antibodies to protect against subsequent infection.

The second is the question regarding the titer of antibodies — a test that measures the quantity and variety of antibodies — and whether this relates to the initial viral load or disease severity. This is relevant given the observed broad Covid-19 spectrum, with mild or asymptomatic disease on the one hand, and the more severe variety on the other, with overlapping clinical symptoms in between. A study published in Nature revealed that antigen burden is indeed a major driver of the magnitude of the immune response. The highest titers of neutralising antibodies were noted in recovered patients with more severe disease. Those with mild or asymptomatic disease ended up having antibodies with not only low titers but also low viral neutralising activity against the receptor binding domain (RBD) of the viral S protein.

The third important issue relates to the cellular arm of the adaptive immunity to Sars-CoV-2, critical both for vaccine development and for instituting infection control measures. Like antibodies, the magnitude of T-cell response, encompassing both helper and killer T-cells, is also discordant among individuals and influenced by disease severity. Early on in the infection, virus specific T-cells start to appear reaching their peak within two weeks. However, their numbers start to decline in six to seven weeks by which time IgG antibody reaches its peak. Like antibodies, Sars-CoV-2 specific memory T-cells are generated across the disease spectrum, which remain in circulation in small but sufficient numbers for long periods, and mount a more aggressive recall response on further exposure to the same virus or during vaccination. They also exhibit antiviral cytokines and cytotoxic activities which are necessary for preventing recurrent severe infection. This might explain why re-infection in coronavirus is not common, barring a couple of anecdotal reports of mild illness.

The fourth is the issue of “cross-reactive immunity” between different coronaviruses since this will have a bearing on planning vaccination strategies. Using multiple experimental approaches, a paper published in Cell identified memory T-cells in almost 100% of patients recovering from Covid-19. These investigators were able to detect Sars-CoV-2 reactive helper T-cells in 40%-60% of healthy, unexposed individuals, suggesting cross-reactive T-cell recognition between the circulating “common cold” coronaviruses and SARS-CoV-2. Whether these cross-protective T-cells can prevent SARS-CoV-2 infection remains to be determined. But experts argue that any degree of cross-protective coronavirus immunity in the population could have an impact on the overall course of the pandemic and the dynamics of epidemiology for years to come.

The fifth question is how and when herd immunity can be achieved and at what cost. It literally means at least 50% of the population needs to get immune to the virus, either through overcoming natural infection or through vaccination, so as to stop a further outbreak. Past experience with flu epidemics indicates that natural herd immunity is usually attained with two to three cycles of infection with seasonal strains. Covid-19 does not fall in the same category because with an infection fatality rate of 0.3-1.3%, this could translate into several-fold more infections and at least 10-fold more deaths which would be a high price to pay. Vaccines alone are the safest way to achieve herd immunity to the virus. Until that happens, our safest bet is to adopt the MHD social vaccine — mask, handwash and social distancing — in our daily lives.

Narinder Kumar Mehra is Indian Council of Medical Research emeritus scientist (Hon) and former dean of the All India Institute of Medical Sciences, New Delhi

The views expressed are personal

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