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COVID-19 Natural Immunity vs Vaccine Immunity

Updated: Jun 13, 2021

COVID-19 vaccines are effective and induce a strong immune response. Cure-Hub's own data shows high neutralizing antibody levels after vaccination, especially after the second mRNA dose. In fact, two doses of the Pfizer and Moderna vaccines can push antibody production higher than natural infection (Vaccines vs Natural Infection | Cure-Hub).

However, this does not mean vaccine induced immunity is superior to natural immunity. Below we provide evidence that recovery from natural infection generates a more diverse immune response.


There are 5 proteins encoded in the viral genome: Nucleocapsid (N), Spike (S), Hemagglutinin esterase (He), Membrane (M) and Envelope (E).

The most important protein is S, which the virus uses to enter human cells. By blocking S, SARS-CoV-2 cannot bind to the human ACE2 receptor and cannot cause an infection.

Due to S protein's critical role in COVID-19 infection, it is the target for Pfizer, Moderna and J&J COVID-19 vaccines. Specifically, those vaccines are designed against the S protein receptor binding domain (RBD), which is the part that interacts with human ACE2.

After vaccination your body produces antibodies that bind to S RBD. As a result you are protected from infection because the virus is neutralized before viral replication occurs.

People who recover from a natural infection are also protected, because they too produce antibodies against S RBD. In fact, that is the immune system's dominant target after infection.

The key difference between the Pfizer, Moderna and J&J vaccines, and natural immunity, is the immune system's starting material. With all three vaccines your immune system is only exposed to S RBD, therefore S is the only target available for an immune response.

However, during natural infection your body is exposed to the entire virus, which includes the other 4 proteins coded in the SARS-CoV-2 genome.


Cure-Hub Data

The variation in starting material has real world effects and our new data shows that natural infection induces antibody production against N protein in addition to S RBD, whereas vaccinated individuals only respond with S RBD antibodies (Figure 1).

If we group vaccine antibody responses against natural infections, then we see a clear difference (Figure 2).

The data indicates a greater than 2 log increase in nucleocapsid IgG antibody signal after natural infection (median log2 MFI = 8.45) compared to pre-exposure or post-vaccination antibody levels (median log2 MFI = 6.38 and 6.36, respectively).

Individual immune responses display this phenomenon very well (Figure 3). Similar nucleocapsid and spike antibody data has been reported in recovered individuals.

While both immune events produce antibodies against S RBD, only natural infection induces antibody production against nucleocapsid.


About Nucleocapsid

Nucleocapsid is a protein involved in genome packaging and viral assembly. It is not found on the surface of SARS-CoV-2.

S, however, is found on the virus surface, which is the reason it is the dominant immune target after infection.

Due to the greater immune pressure it receives, S protein mutates more rapidly than nucleocapsid. When variants are discussed, the implied variation is in the S protein.

The reduced immune pressure on nucleocapsid helps conserve its sequence and structure, which could mean nucleocapsid antibodies retain effectiveness against emerging SARS-CoV-2 variants.

"It appears that the N protein is conserved across the variants of SARS-CoV-2 and SARS-CoV-1."
- Deb Kelly, Huck Chair in Molecular Biophysics and director of the Penn State Center for Structural Oncology.


Cure-Hub's data and other written reports suggest natural immunity may provide broader immune protection than vaccination.

This is important because some states, such as Oregon, only count vaccinated individuals in their criteria for lifting economic lockdown orders.

Despite this, many research groups have shown recovery from SARS-CoV-2 infection is protective against reinfection. For example, this report shows a 96.7% reduction in reinfection in people who previously had COVID-19.

By ignoring the role of natural immunity, states like Oregon prolong economic, educational and societal damage.



The work presented here, in combination with other reports about immune protection in recovered individuals, provides justification for including natural immunity in COVID-19 herd immunity stats. It is important to remember the immune system is complex and has redundant and overlapping mechanisms. Antibody production against both the SARS-CoV-2 N and S proteins is just one example. The vaccines are indeed very effective, but so too is the human immune system. It would therefore be anti-science, and anti-data, to ignore the role that recovery from COVID-19 plays in protecting against reinfection and ongoing viral spread. Especially when deleterious decisions are being made in order to mitigate COVID-19 risk.

-This report was written by Ian Martiszus


After screening and informed consent was completed on Cure-Hub's online platform, study participants were mailed a home sample collection kit. Thank you to all who have participated, you helped everyone better understand COVID-19.

Original data in this report was generated in collaboration with CDI Labs, who ran the samples on their SARS-CoV-2 2-in-1 antibody array. Thank you, CDI Labs.

If you would like to participate and receive a COVID-19 neutralizing antibody test, then click the sign up button below. Or you can click donate to support Cure-Hub's independent research without submitting a sample.

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1 Comment

What clinical advantage can be proposed for having N-protein antibodies? Due to imperfect viral replication and assembly, N-protein would end up in the blood and interstitial fluids where antibodies operate. But the N-protein within infected cells and within intact viruses would not be accessible to N-protein antibodies. In other words, why is N-protein immunity important towards future infection / re-infection?

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