In a recent article published in Immunity, the authors discussed the underlying principles of sterilizing immunity and its importance in protecting individuals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfections during the coronavirus disease 2019 (COVID-19) pandemic.

Background

During an infection, the B and T cells of the immune system launch an adaptive immune response by secreting serum antibodies and killing infected host cells, respectively. While the serum antibody levels decrease after the infection, plasma cells in the bone marrow continue to produce antigen-specific antibodies for a long time.

Upon re-encountering the same pathogen, the memory B cells developed during the earlier infection can rapidly increase the antibody titers against the pathogen. The immune response mounted by the plasma cells and memory B cells during reinfection are much more potent and faster, often eliminating the pathogen before the disease becomes symptomatic or severe.

However, with viruses, the second encounter is often with a mutated variant of the earlier virus, making it difficult for the high-affinity antibodies formed by the memory immune response to recognize and neutralize the pathogen.

Sterilizing immunity

Sterilizing immunity prevents the pathogen from infecting the host by eliminating it before it can enter and replicate in the host cell, ideally at the site of entry. Since early reinfections are generally asymptomatic and low pathogenic levels during re-infections under the activity of the memory immunity are hard to detect, distinguishing sterilizing immunity from the protective immune memory is difficult. The absence of clearly defined parameters or correlates with measuring sterilizing immunity adds to the difficulty.

Vaccines present the immune system with attenuated pathogens, or antigens consisting of structures on the pathogen surface to generate a mild adaptive immune response and a long-lasting memory immune response. Booster vaccinations reintroduce the antigen to increase the memory response.

The process of antibody affinity maturation generates antibody variants mediated by random mutations, which exhibit improved antigen binding. The high-affinity antibodies developed through affinity maturation prevent viruses from invading host cells by binding to and blocking the virus receptor sites on the host cell surface, mediating sterilizing immunity.

Immune escape

Pathogens have developed immune escape strategies to avoid the host’s adaptive and innate immune responses and continue transmission from host to host. Bacteria and parasites generate diverse antigens through changes in gene expression, while viruses mutate or perform the antigenic shift. Antigenic shift results in genome fragment exchanges between two viruses infecting the same host cell. The antigen diversity in pathogens reduces the efficacy of vaccines.

The antibody responses in the host cell also exert selection pressure, resulting in the survival and transmission of viruses that can survive the host cell’s immune response. However, antibodies that target conserved regions of the virus or other pathogen can effectively neutralize newly emergent variants of the pathogen. Broadly neutralizing antibodies are formed as part of the affinity maturation process, but the induction of broad neutralizing antibody responses through vaccines has proven difficult.

COVID-19 and sterilizing immunity

The absence of prior immunity to SARS-CoV-2 resulted in the rapid global spread of COVID-19 and caused serious outcomes, including high mortality worldwide. The global push to develop vaccines successfully limited the spread and severity of the disease.

Vaccines and antibody therapies largely targeted the spike protein and receptor binding domains of SARS-CoV-2. However, the emergence of immune-evading SARS-CoV-2 variants is a prime example of host-pathogen co-evolution, with the emergent variants eliminating the previous strains and gaining global dominance.

Nevertheless, the memory responses developed from vaccines and previous infections with older variants successfully protect individuals against severe outcomes of COVID-19, even during infections with the new mutated variants. Studies indicate that this cross-protection is most likely due to broadly neutralizing antibodies against the relatively conserved regions of the receptor binding domain.

According to the authors, sterilizing immunity in the context of SARS-CoV-2 will be difficult to achieve unless vaccine- or infection-induced immunity generates broadly neutralizing antibodies or the rate of viral evolution decreases. To inhibit viral invasion at the site of entry, humoral responses in the upper respiratory tract need to be stronger, and vaccines have not been successful in generating potent immune responses in the mucosal layers.

Conclusions

To summarize, the authors discussed how booster vaccinations and exposure to pathogens could generate strong memory responses, establishing sterilizing immunity through broadly neutralizing antibodies produced by the affinity maturation process. However, pathogen evolution and antigen diversity challenge achieving sterilizing immunity.

The rapid transmission and large viral reservoirs of SARS-CoV-2 result in newly emergent, immune-evading variants. The inability of COVID-19 vaccines to generate broadly neutralizing antibodies indicates that sterilizing immunity in the context of SARS-CoV-2 will be difficult to achieve. However, cross-reactive immunity from vaccinations and previous infections continues to exhibit some protection against severe infections from emergent variants.

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.