Robust immunity against SARS-CoV-2 with Pfizer vaccine is mediated by memory B cells

A reassuring study, released as a preprint on the medRxiv* server, from a multi-institutional team of researchers in Italy suggests that with the Pfizer-BioNTech BNT162b2 vaccine, post-vaccination immunity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is both robust and durable.

This is because even though antibody-mediated immunity wanes over time, specific memory B cells are induced after the first dose that increases significantly after the second. These cells increase over time, even two months from the second dose, indicating that the vaccine induces strong and sustained protection.

Background

Not only antibodies but also specific memory B cells are induced by the Pfizer vaccine. These biomarkers were detectable after one dose but increased markedly after two.

At two months from the first dose of vaccine, virus-specific antibodies had declined, but memory B cells continued to show an upward trend.

The vaccine does not induce a rise in mucosal immunoglobulin A (IgA) immunity, which protects the respiratory and oral cavities against infection with the virus. However, the researchers found that with the induction of memory B cells against SARS-CoV-2, they eventually migrated into the mucosa at these sites in response to local inflammation.

This migration was henceforward associated with the secretion of IgA at these surfaces.

One dose or two doses of COVID-19 vaccine?

A single dose of vaccine is apparently inadequate for specific memory B cell immunity. The vaccine recipient remains vulnerable to infection, rather than rapidly clearing the virus with the help of class-switched antibodies before it has a chance to establish infection and spread to other hosts.

The efficacy of a single dose thus seems to be lower than that of the full regimen due to an incomplete immune response. This supports the objections to single-dose regimens by epidemiologists, who fear that this may encourage new variants to emerge by selecting for immune-escape mutations.

This can also reduce the degree of protection offered by currently available vaccines and those in the pipeline, since the viral spike protein that forms the basis of these first-generation coronavirus disease 2019 (COVID-19) vaccines has undergone several changes under selective pressures.

Despite this, the need to reduce the population risk of severe and fatal illness due to COVID-19 has led to the increasing use of a delayed-second-dose regimen. The intention is to expand the population covered by at least one dose, and therefore the pool of people with some immunity to the virus.

However, following two doses, even though sterile immunity is not induced by the vaccine because mucosal IgA is not induced, the vaccine remains protective against COVID-19, irrespective of falling antibody levels.

The role of memory B cells in immunity

The researchers point out that the decline in the short-term antibody response is not unique to COVID-19. The cooperation of memory B cells and memory plasma cells is more important in long-term immunity, preventing reinfection (or primary infection, in the case of successful vaccination).

Memory plasma cells turn out virus-specific antibodies that can neutralize the virus before it establishes host cell infection. Simultaneously, memory B cells leave the blood to enter the site of inflammation induced by viral entry to secrete antibodies there as well. Depending on the affinity of binding of the antibodies, the virus may be cleared at first sight.

T cells promote the production of antibodies with high affinity for the viral antigens, as well as the maturation of some of the B cells into the memory phenotype. They also act as direct effector cells, ultimately killing the cells infected by the virus.

How is the second dose crucial to rapid viral clearance?

The study included 108 healthcare workers, in whom specific memory B cells were measured at and seven days after each dose of the vaccine and three months after the first dose.

The researchers found that the immune memory generated by a single dose is relatively imprecise and cannot clear the virus rapidly. This is responsible for the lower vaccine efficacy at this point.

With the second dose, a markedly higher proportion of people became vaccine responders, with dramatically higher antibody levels a week later, and importantly, higher memory B cells.

The antibodies targeted the receptor-binding domain (RBD) as well as the spike protein, with the IgG levels of each rising 60 and 8 times, respectively, within a week of the second dose. Neutralizing activity increased 25 times over the same period.

While antibody levels fell to half by three months, the number of memory B cells continued to rise. These were shaped within the lymph node germinal centers by the processes of somatic mutation, affinity maturation and class switching.

This resulted in the production of more antigen-specific and high-affinity antibodies as well as memory B cells and plasma cells that generate antibodies capable of eliminating the pathogen from the body and ending the infection.

The adaptive immune response triggered by the vaccine needs time and is strongly selective,” say the scientists.

Moreover, these cells produced IgA antibodies in the serum but not in the mucosa, which is responsible for the lack of sterilizing immunity. At any point, about a tenth of IgM memory B cells were able to produce anti-spike binding antibodies, indicating their role as the primary adaptive defense cells and the rapid action force for the production of class-switched high-affinity specific memory B cells.

Only 0.5% of these became IgG secreting cells, and even less (<0.1%) became IgA-secreting cells by day 28, remaining at similar levels at day 90. Some of these cells gained anti-RBD specificity, contributing to their neutralizing capability.

Breakthrough infections were mild and short-lived

While 21/3,511 vaccinated workers had a positive swab test after both doses had been taken, none had symptoms beyond those of mild illness (fever, cough and muscle pain). In six cases that were studied, IgA in saliva was detected by six days from the diagnosis by swab positivity and increased further, though at ten times lower levels than in serum.

This suggests that “vaccine-induced [memory B cells] have performed their job by rapidly migrating to the site of viral invasion.” This led to the elimination of the infection at an early stage, and the low viral load in such individuals may prevent transmission of the virus to others even during this period.

No worker with a history of COVID-19 prior to vaccination developed a reinfection, and all had detectable IgA in saliva, indicating their mucosal immunity against the virus at first entry. Mucosal vaccines may well be the way to go in eliminating infection with this virus altogether.

Examining two of the 21 post-vaccination infections, one worker had low levels of highly specific affinity-matured memory B cells even at day 28, but were 23 times higher by day 70 from the first dose. The other had both low and high-affinity specific memory B cells at day 28, with a dramatic rise in their number at two weeks after the positive swab at day 110.

Similar increases in memory B cells were found following a mild infection, confirming that this occurs in response to the virus. In these cases, the powerful mucosal protection resulting in the swab becoming negative two days after the first positive swab is thought to indicate a prior asymptomatic infection that went undetected but produced mucosal immunity.  

What are the implications?

For all these reasons we should not worry about the antibody decline in the serum. Our MBCs are our most important defense weapon that ensure local and systemic protection after re-encounter with the antigen,” write the authors.

The mRNA vaccines produce a strong and durable immune response against the virus, when two doses are used.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.