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SARS-CoV-2 Vaccines, Breakthrough Infections and Lasting Natural Immunity

Updated: Aug 22, 2021

SARS-CoV-2 Nucleocapsid and Spike 3D Cryo-EM Images
Photo from InVivo Biotech.

Emergence of SARS-CoV-2 variants is now the focus of the SARS-CoV-2 pandemic. Today, the Delta variant is notable due to its rapid dominance in all sequenced COVID-19 cases. Vaccines induce a strong immune response against the wild type (WT) variant, but there are now reports of breakthrough infections in vaccinated individuals.

The breakthrough infection rate reported by the American CDC is low. Despite the existence of these infections, severity and transmission appears to be reduced in fully vaccinated individuals (1, 2, 3).

While much attention has been on breakthrough infections, there is less focus on reinfections in people with natural immunity.

The data exists and multiple studies show that reinfection in people with natural immunity is rare. Data also suggests that natural immunity is more protective than vaccine related immunity (1, 2, 3, 4).

Similar to breakthrough infections in vaccinated people, when reinfection does occur in a recovered individual, the majority of time it is asymptomatic.

Below we use original data from Cure-Hub's antibody study to explain why the vaccines offer transient full immunity but still provide lasting partial immunity. Then we show how natural immunity provides broad immune protection that may be longer lasting against SARS-CoV-2.

Protein Background

The SARS-CoV-2 genome encodes for 5 proteins, which are made of chains of amino acids. For example, the virus uses the 1,273 amino acid long Spike (S) protein to infect human cells. When a COVID-19 variant is discussed, the implied variation is in S amino acid sequence. In fact, S is the only protein mentioned on the CDC's variant webpage.

You can break full length proteins into smaller fragments, called peptides, and more precisely study immunity. This allows you to tease apart vaccine and natural infection antibody responses.

Variant Background

Variants have specific amino acid changes. For example, the Delta variant contains about 13 amino acid changes in S, compared to WT. These changes allow the virus to sometimes escape from antibody binding.

Antibodies bind to small 5-15 amino acid segments called epitopes. That means several distinct antibodies can target a full length protein. The vaccines induce an immune response against S receptor binding domain (RBD), which provides many epitope targets for antibodies. However this is not the only region of full length S protein that induces an immune response. Nor is S the only SARS-CoV-2 protein targeted by your immune system in natural immunity.

Results: SARS-CoV-2 Antibody Signatures

Cure-Hub's data indicates strong antibody production against the SARS-CoV-2 spike protein after vaccination and natural infection. However, natural infection tends to produce antibodies against a greater number of targets. In fact, the 3 individuals with the most antibody targets post-immune event had a natural infection (Figure 1)

Two natural infection super responders have antibodies against peptides across the spike protein. The other 2 natural infections have around the same spike protein antibody diversity as those who received the vaccine (Figure 2).

The most significant difference between vaccinated and naturally infected individuals is the antibody response against nucleocapsid (N) protein (Figure 3). There is no increased signal after vaccination, but each of the naturally infected individuals has a strong antibody induction against N. Some naturally infected individuals also have hints of antibody production against SARS-CoV-2's ORF and NSP proteins.

Virscan Results: Cross Reactive Antibodies To Other Betacoronaviruses

When we compare antibody binding to proteins on other coronaviruses, there appears to be a slightly higher number of unique antibody targets in naturally infected individuals (Figure 4).

However grouping the vaccines shows 2 more unique peptides in the composite vaccine group (n=6), than natural infection (n=4). This slight difference could be noise in the data.

For example, both J&J and one Moderna vaccinated individual had elevated antibodies against the endemic coronavirus, HKU1. Interestingly two of the three seemed to respond to HKU1's membrane protein and the third responded to nucleocapsid.

Antibodies made after SARS-CoV-2 natural infection or vaccination have strong binding to the Spike protein on several other coronaviruses (Figure 5).

Both vaccination and natural infection induce S antibodies that recognize the original SARS. This means that if you were vaccinated or have natural immunity against SARS-CoV-2, then you might also be protected against SARS-CoV-1.

In naturally infected individuals, N antibodies from SARS-CoV-2 natural infection also bind SARS-CoV-1 nucleocapsid protein.


Considering the global distribution of over a hundred million cases, SARS-CoV-2 now appears to be an endemic virus.

Rapid and unpredictable mutation of RNA viruses means it will be difficult to keep vaccine design and production on pace with viral evolution. This raises questions about a vaccine's ability to offer full, long term protection against SARS-CoV-2 variants, even with booster shots.

Cure-Hub's data shows less antibody diversity in vaccinated individuals than naturally infected individuals. Fewer unique antibodies provide the virus with an avenue for immune escape through S protein mutations.

Antibodies against N offer an additional layer of protection for naturally immune individuals. The N protein is reported to have a slower mutation rate than S, which further reduces susceptibility to SARS-CoV-2 variants. In naturally immune individuals, antibodies against S and N are also cross reactive against other coronaviruses. This demonstrates the broad antibody repertoire generated after a natural infection.

A variant may escape some but not all antibodies produced after vaccination. Due to reduced antibody coverage, vaccinated individuals could get a breakthrough infection. For most, that breakthrough infection will be less severe than if they had no antibody coverage. Antibodies that cross react against S protein found on other coronaviruses is an additional benefit of vaccination.

When you do have natural immunity you will have more comprehensive antibody protection. After almost everyone has some natural immunity, it will be more difficult to transmit the virus.

It is unclear how long natural immunity lasts in an endemic SARS-CoV-2 setting. The pathogenicity of the virus is also unknown after broad natural immunity is reached. It is possible that our endemic 'common cold' coronaviruses like HKU1 and OC43 were once deadly pathogens but have now become mostly benign, albeit annoying yearly infections. Perhaps this is the long term trajectory for SARS-CoV-2.

Cure-Hub suggests discussing questions you have with your physician. We do not support purposeful inoculation with SARS-CoV-2. We wouldn't even do that for a common cold.


Antibody Arrays Used For This Report

To evaluate IgG antibody responses, we ran samples on CDI Labs COVID-19 2-in-1 array to measure antibody binding to SARS-CoV-2 proteins and S peptides.

In total the COVID-19 2-in-1 array contains individual spots for these full length proteins and subunits:

  • S1, S2 and RBD,

  • Nucleocapsid and its N and C-terminus subunits

  • ORF,

  • NSP,

  • Envelope (E) and

  • RdRp

Spots for 12-amino acid long peptides from Spike's S1 and S2 subunits are also on the chip. In total there are 119 unique S1 peptides and 91 unique S2 peptides.

The 2-in-1 array is one of the most comprehensive tools available to assess antibody signatures following COVID-19 vaccination or infection. Antibody binding values from this array are in mean fluorescence intensity (MFI).

CDI Labs offers a similar array called the Virscan, which measures antibody binding to proteins on many known viruses. Each sample in this report was also run on that array. The IgG data was used to assess antibody binding to other known betacoronaviruses after SARS-CoV-2 vaccination or natural infection. Values from the Virscan are not directly comparable to the COVID-19 2-in-1 array. Virscan values are the number of 'Hits,' which are a measure of fold change compared to controls.


Samples came from six vaccinated and four naturally infected individuals. The Pfizer, Moderna and J&J vaccine groups each have two individuals with pre- and post- samples.

The natural infection group has pre- and post- samples from two naturally infected individuals. Two other individuals provided post infection samples but did not have a pre-infection sample. For each peptide, individuals with only a post-infection sample were compared to the average for all pre-immune event samples.

One more pre/post sample set is included from someone who was uninfected after a direct exposure by their spouse. The uninfected individual had two negative PCR tests and tested negative for antibodies with Genscript's cPASS neutralizing antibody kit.


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.

Thank you to CDI Labs, who ran the antibody arrays for this project.

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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