What is the long-term protection against COVID-19?


The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is known to cause numerous clinical manifestations. Little is known about the protection conferred by prior infection or vaccination against long-term infection.

A new paper in Immunological examinations describes the immunological parameters associated with protection against COVID-19.

Study: COVID-19 and plasma cells: is there long-term protection? Image Credit: Sutthituch/Shutterstock


Humoral immunity is associated with long-lasting protection against infections thanks to the neutralization of the infectious agent by antibodies. These neutralizing antibodies (nAbs) are secreted by long-lived plasma cells (LLPC). While long-lasting protection was the norm with the earlier pandemic virus, H1N1 influenza, antibody protection against COVID-19 after infection with SARS-CoV-2 is short-lived, leading to reinfections.

Contact with SARS-CoV-2 antigens activates naïve B cells, which become activated and transform into antibody-secreting cells (ASCs). These produce low affinity antibodies, mainly immunoglobulin M (IgM), characteristic of the early phase of infection.

Some ASCs undergo further maturation in the germinal center (GC) of the lymph node to become high-affinity ASCs, or alternatively memory B cells (MBCs), and end up as LLPCs. This second phase is GD-dependent and leads to the appearance of durable, high-affinity, class-switched, pathogen-specific IgGs and IgAs.

ASCs typically make up less than one-hundredth of circulating B cells, increasing to as much as one-tenth in acute viral infections. For a few viruses, including the dengue and hantavirus pathogens, ASCs can represent up to 80% of all B cells.

Over time, ASCs die rapidly, but MBCs from some long-lived tissue sites, especially bone marrow (BM), continue to differentiate into ASCs and then into tissue-resident LLPCs, under the influence of locally active transcriptional and epigenetic factors. These two types of cells produce memory antibodies for much longer.

LLPCs are very rare and have a different phenotype from other ASCs. Not only do they live much longer than early ASCs, but they are extremely energy efficient, resist apoptosis, and thus continue to produce antibodies specific to the cognate antigen throughout life.

The current paper examines the responses of human LLPCs following natural SARS-CoV-2 infection or vaccination, as far as is known today, using previous research.

Early peak and decline in AUCs

After the first infection with SARS-CoV-2, the first ASCs respond within a few months, although there is a large interindividual variation in antibody titer.

In HIV-positive patients, nAb titers correlate with total and anti-RBD antibody titers, both of which peak in 3-5 weeks and halve in 8-13 weeks. IgG at peak and RBD correlate with catches, peak within months, and slowly decay within a year.

Older men who required hospitalization for COVID-19 had higher antibody titers. Severe COVID-19 has been associated with rapid antibody spikes just days after symptom onset, with early class-switched neutralizing responses, occurring through a non-canonical pathway.

In severe and critical infection, GC function is impaired and large early ASC responses predominate, related to the extrafollicular (EF) B cell response. These can give rise to several highly specific traps. GC B cell responses have also been demonstrated in mild and severe infections.

Antibodies decline 5-10 fold at 5 months, although they remain detectable at low levels for up to 12-20 months. However, IgM and IgA decline much faster than IgG. Antibodies against the SARS-CoV-2 core (N) antigen break down faster than those against the spike (S) or receptor binding domain (RBD). The former may be undetectable approximately one year after infection, while the IgG spike remains detectable.

Some patients never seroconvert, apparently, ranging from 5 to 33%.

Also after vaccination, an early IgM, IgA and IgG response sets in and GCs are active for months. The ASC response is however more attenuated compared to natural infection, probably because the vaccines contain only 5 epitopes. Vaccine-induced NTAs are considered a marker of vaccine efficacy.

Vaccine-induced antibodies also peak early, but B cells quickly enter apoptosis within a week. The decrease in nAb titers is evident at 3-10 weeks and is more pronounced in immunocompromised or very elderly patients. However, the catches are still present up to 8 months after vaccination.

Vaccine breakthroughs occur with new variants, with mutations in spike and other antigenic epitopes, and also possibly because mucosal immunity is absent. However, the severity of the disease in vaccinated people is generally lower. Vaccination confers 90-100% protection against hospitalization and serious infections, and the risk of prolonged Covid is also much lower. T cells primed against the spike antigen by the vaccine can of course contribute to this protection.

A third vaccine booster dose increases vaccine efficacy and accelerates viral clearance, with cross-nAb titers increasing 4 to 73-fold. Hybrid immunity, following a combination of natural infection and vaccination, provides the greatest and broadest protection. Despite the fact that booster vaccine doses contain the wild type rather than the S variant, they increase nAb levels and broaden the range of antibodies.

What about MBCs in COVID-19?

MBCs continue to mature after the virus is cleared from the body, producing unique high-affinity clones and memory antibodies. However, mild and severe disease appears to induce maturation through different pathways.

B cell repertoires in benign diseases show great diversity and abundant mutations consistent with GC activation. Persistence of viral antigens can lead to such an evolution during the year following the initial infection. However, in severe disease, B cells arise from unmutated ASC/MBC clones, derived from EF cells.

Also with vaccination, the primary MBC response is strong and is further increased by the booster dose, leading to the production of cross-nAbs. However, vaccine-induced MBCs do not show much change, although they remain stable in frequency up to 9 months after vaccination.

Antibody protection appears to last less than a year, requiring booster doses at 6 months from primary therapy. Natural and vaccine-induced immunity did not appear to protect against new variants of the virus, leading to repeated infections and breakthrough infections.

Do LLPCs occur in COVID-19?

High affinity “memory” NTAs in serum are the effector molecules of long-term protection.”

The generation of true LLPCs in COVID-19 infection or vaccination, to provide such protection against reinfection is still an open question.

The rapid decline in antibody titers within 4-6 months after the last dose of vaccine appears to rule out the generation of LLPC. Although bone marrow ASCs have been identified by previous researchers, they have not been confirmed as LLPCs.

Short-lived vaccines are usually based on viral antigens, like most COVID-19 vaccines, compared to long-lived vaccines which often contain the whole live virus attenuated.

Can long-term COVID-19 protection be predicted?

Both nAbs and MBCs may be indicators of protection against COVID-19. Long-term protection can only be defined over time, but judging by past coronavirus infections, it is doubtful that long-term protection is available.

There is a hypothetical possibility that the infection will cause a rapid cross-reactive pre-existing antibody response against endemic season human coronaviruses. This could lead to an immuno-imprinting response, where the EF response, although non-neutralizing and poorly protective, dominates the highly specific and neutralizing GC response, with the potential for antibody-dependent amelioration (ADE) of disease. However, studies in this area are very limited.

Autoimmune disease and COVID-19

The dominant EF response pathway of antibody production in COVID-19 could explain autoimmune disease (AID) after resolution of infection. Several studies have confirmed a rapid and large expansion of ASCs, also observed in dengue fever. However, further analysis of the B cell response in severe COVID-19 showed a high degree of similarity to the pattern of B cell activation in chronic AID.

Antibodies produced by these cells also showed reduced peripheral tolerance, with an inherent ability to target self-antigens. Their expression of the IGHV4-34 domain in B-cell receptor genes is unusual because, in good health, these clones are eliminated or transformed by somatic hypermutations (SHM).

Low peripheral tolerance with very low SHM frequencies indicates that “the course of a severe infection may reflect some of the biology previously characterized in the context of an autoimmune disease.” Even with high specificity for the virus, ASCs in severe SARS-CoV-2 infection show a tendency for self-reactivity to nuclear antigens, renal epithelial targets, and naive B cells, despite being far from being invariable.

This suggests that the EF pathway is an accelerated response to severe infection, allowing rapid antibody production and viral clearance. While most of the ASCs so generated are virus-specific, a few can escape central tolerance and expand, resulting in both autoreactive and self-reactive ASCs being present in the mix.

These mixed antibody responses may contribute to the overall inflammatory environment through innate activation and self-targeting to create an anticipation loop of EF response bias.

These autoantibodies may also explain the clotting tendencies, hyperimmune phenomena, and weak antiviral response observed in COVID-19. Some research shows that patients with long-term Covid have autoantibodies that persist beyond the acute period, with longer disruptions in the immune response. However, vaccination against COVID-9 has not been linked to such disruptions.

Long-term Covid risk factors may include autoantibodies, T helper cell type 1 (Th1) bias, type 2 diabetes, SARS-CoV-2 in blood and Epstein virus -Barr in the blood.

A better understanding of the balance between EF and GC responses and the ASC phenotype for the generation and maintenance of LLPC after infection and vaccination is still needed..”


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