How Long Does Immunity Last after Covid? 6 Months or 12?

The novel coronavirus SARS-CoV-2 causes Covid-19 and the associated pandemic remains difficult to control, even though there are several effective vaccines. This difficulty is due to the emergence of more transmissible and seemingly more antibody-resistant variants.

Nature reports new research showing that, in people who previously had Covid-19 and have not been vaccinated, the binding of the SARS-CoV-2 virus to the receptor-binding domain (RBD) on the surface of human cells is blocked by B cells whose numbers remain relatively stable between 6 and 12 months. B cells do this through the neutralizing antibodies they produce against the coronavirus receptor-binding domain. This antibody response is called the immune system’s humoral (fluid-mediated) response.

Explanation of the figure: B cells are naturally present in the body. There are B cells with a variety of antibodies. To conserve both energy and resources, they do not multiply unless needed. A pathogen entering the body for the first time is highly likely, depending on its effect, to evade the innate immune system. An antigen that gets past this system binds to a B cell already present in the body whose antibody is complementary to it, causing that cell to multiply. This specific, pathogen-directed multiplication is called clonal expansion. When B cells have multiplied sufficiently, they divide into two subgroups: plasma cells and memory B cells.

New information

Previously, immunity in people who had Covid-19 was estimated to last 4-6 months, but information about the subsequent period was unclear. In this new study, neutralizing antibody levels in most patients were observed to plateau (remain stable) after month 6.

Vaccination is now known to produce a stronger humoral response than infection; it increases all components of the humoral response and, as expected, results in serum-neutralizing activities against relevant variants that are comparable to, or broader than, the neutralizing activity against the original Wuhan Hu-1 achieved by vaccinating uninfected individuals. The mechanism underlying these broad responses includes continued antibody somatic mutation, memory B-cell clonal turnover and the development of monoclonal antibodies remarkably resistant to SARS-CoV-2 RBD mutations, including those found in relevant variants. In addition, B-cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand dramatically after vaccination. The data show that immunity in convalescent individuals will be very long-lasting and that those who receive current mRNA vaccines and are convalescent will produce circulating antibodies and memory B cells that should be protective against SARS-CoV-2 variants.

Memory B cells formed against coronavirus

B cells activated during an immune response interact with T cells of the same origin and begin dividing before being selected for division into plasma cells, memory cells or germinal-center B cells, partly according to their affinity for the antigen. B cells expressing high-affinity antibodies are favored for entry into long-lived plasma-cell divisions, whereas memory-cell divisions are more diverse and can develop directly from activated B cells or from a germinal center. Memory cells originating from a germinal center carry more mutations than those developing directly from activated B cells because they undergo additional cell divisions.

The structure of a lymph node where B cells are produced is shown below:

SAR-CoV-2 infection leads to persistent serum anti-RBD antibodies and corresponding neutralizing responses. Approximately 93% of plasma-neutralizing activity is retained between 6 and 12 months. Vaccination increases the neutralizing response 1.5-fold by triggering additional plasma-cell differentiation from memory B-cell division. The strengthening of evolved memory B cells producing antibodies with broad and potent neutralizing activity in plasma-cell division most likely accounts for the exceptional serological activity of vaccinated convalescent people against relevant variants.

Little is known about selection and maintenance of memory B-cell division. SARS-CoV-2 infection causes memory-cell division that continues to develop 12 months after infection through the accumulation of somatic mutations, the emergence of new clones and increasing affinity. All of this is consistent with prolonged persistence of the germinal center. The increase in activity against SARS-CoV-2 mutants parallels the increase in affinity and is consistent with findings that increasing the apparent affinity of anti-SARS-CoV-2 antibodies through dimerization or generating specific antibodies also increases resistance to RBD mutations.

Epitopes and breadth of neutralization

Continued antibody evolution in germinal centers requires antigen that can persist in these structures for a long time. SARS-CoV-2 protein and nucleic acid have also been reported in the intestinal flora for at least 2 months after infection. Regardless of the antigen source, antibody evolution helps epitopes (regions of antigens that bind to antibodies) overlapping the ACE2-binding site on RBD, probably because these are epitopes exposed on the trimeric spike protein or virus particles.

Vaccination after SARS-CoV-2 infection

Vaccination after SARS-CoV-2 infection sequentially increases the number of RBD-binding memory cells by recruiting new B-cell clones into memory and expanding persistent clones. Persistent clones expand without accumulating many additional mutations, indicating that clonal expansion of human memory B cells does not require re-entry into germinal centers and occurs through activated B-cell division.

The substantial development of breadth after infection and the potent improvement in serological responses and B-cell memory achieved with an mRNA vaccine suggest that vaccinated convalescent individuals should benefit from high levels of protection against emerging variants without needing changes to current vaccines. If memory responses develop similarly in vaccinated, previously uninfected individuals, appropriately timed additional doses of current vaccines should produce protective immunity against circulating variants.

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