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

Updated: Aug 22


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.

Discussion

Considering the global d