How does natural immunity to SARS-CoV-2 infection differ from immunity generated by COVID-19 vaccines?

Biology/Immunity Vaccines

A. COVID-19 vaccines induce higher levels and a broader range of neutralizing antibodies to the receptor binding domain (RBD) of the spike protein than does natural infection. Vaccine-induced antibodies are less likely to be affected by changes in the RBD seen in the current SARS-CoV-2 variants, and are therefore more likely to be more effective against variants.

➡️ TL;DR. The receptor binding domain (RBD) of the SARS-CoV-2 spike protein binds to ACE2 receptors on human cells, allowing the virus to enter. A robust neutralizing antibody response against the RBD is critical for protection against infection. While both natural infection and COVID-19 vaccines induce neutralizing antibodies to RBD, COVID-19 vaccines induce a much LARGER VARIETY of neutralizing antibodies to RBD than does natural infection. What does this mean for immunity to SARS-CoV-2 infection? Vaccine-induced antibodies can bind to MANY more places on the RBD than natural infection-induced antibodies can and may therefore be more effective in blocking the virus (and its variants) from entering human cells.

❓ Why are RBD antibodies important? The SARS-CoV-2 spike antigen’s ‘receptor binding domain’ or RBD is essential for the virus’ entry into human cells. The RBD binds to ACE2 receptors on human cells, allowing the virus to enter cells, where it multiplies and causes cellular destruction. The immune system responds to SARS-CoV-2 infection by making antibodies that recognize the virus. While antibodies are made to many different parts of the virus, the ones that recognize the RBD are critical for protection. These ‘neutralizing antibodies’ disrupt RBD-ACE2 binding and prevent the virus from entering human cells. COVID-19 vaccines are designed to present the RBD to the immune system in order to make RBD-specific neutralizing antibodies, and thereby block the virus from entering cells.

❓ Are vaccine-induced and natural infection-induced RBD antibodies identical? Although RBD antibodies are made in response to natural infection and vaccination, they do not appear to be identical. Researchers studied the antibody response made to COVID-19 mRNA vaccines and to natural infection with SARS-CoV-2. They found that vaccine-induced RBD antibodies recognized many different parts of the RBD, whereas natural infection-induced antibodies recognized fewer parts of the RBD. Natural infection also induced antibodies to many other parts of the SARS-CoV-2 spike protein as well as other viral proteins, whereas the majority of the vaccine-induced antibody response was focused on the RBD. Furthermore, researchers noted that the vaccine-induced RBD-specific antibody response was MUCH higher than the RBD antibody response following natural infection (Link to study below). Although this study was specific to mRNA vaccines, real world data shows that the adenoviral vector vaccines (Johnson & Johnson and AstraZeneca) are also effective to varying extents against SARS-CoV-2 variants, which suggests that these vaccines also might induce a broader response to the RBD.

❓ Why is this difference important? SARS-CoV-2 variants bear small changes in the RBD protein sequence. Although these changes are small, they can result in variants that are much more transmissible and infectious – as we’re seeing in the case of the Delta variant. Because vaccine-induced RBD antibodies recognize many different parts of the RBD, they have a better chance of continuing to be effective against new variants, and continuing to bind to the RBD protein in spite of the changes in protein sequence. The combination of high titer and ‘broadly neutralizing’ RBD antibodies induced by vaccination is highly effective against preventing infection in the majority of vaccinated people, and IMPORTANTLY, preventing severe disease.

❓ Why are natural immunity to SARS-CoV-2 and COVID-19 vaccine-generated immunity different? It is not clear as yet; it’s possible that (1) the way COVID-19 vaccines (whether mRNA or adenoviral vector based) present the RBD to the immune system compared with RBD presented by natural infection results in differences in the antibody response; (2) the shape of the RBD in the vaccine may be slightly different from the virus’ RBD; or, (3) the route of the RBD entry is different – vaccines are injected into muscle where the immune system has a better chance of seeing the RBD and making a response to it, compared with natural infection where the virus enters the body through the airways.


👉🏽 COVID-19 vaccines induce a robust immune response that is effective against the original SARS-CoV-2 virus as well as, to varying extents, against current variants in circulation.

👉🏽 IMPORTANTLY, COVID-19 vaccines DO protect against severe disease and death.

👉🏽 Vaccination induces a more uniform and predictable immune response than does natural infection.

👉🏽 AND, developing immunity through natural infection brings with it the risk of severe disease or the consequences of long COVID.

Stay safe! Get vaccinated!

Those Nerdy Girls

📚Further reading:

(1) Differences between COVID-19 vaccine-generated immunity and infection-generated immunity:

NIH Director’s Blog

News Medical Life Sciences

(2) Study showing COVID-19 vaccines induce much higher titers of RBD antibodies

(3) Research shows that antibodies produced by vaccination recognize many more parts of RBD compared with natural infection.

(4) On getting vaccinated after COVID-19 infection

(5) More about variants and vaccines

(6) Vaccine efficacy and the delta variant

Link to Original FB Post