Natural and Vaccine Immunity Against the SARS-CoV-2 Endemic Virus.

On March 11th, 2020, the World Health Organization (WHO) declared COVID-19 a global pandemic. In the United States, our ability to combat SARS-CoV-2 virus was greatly accelerated by Operation Warp Speed. The incredible speed with which vaccines got to the public is a testament to human innovation, demonstrating what the biotech industry can achieve when regulatory reins are loosened.

Data from an ongoing SARS-CoV-2, nationwide antibody study by Cure-Hub LLC shows high neutralizing antibody levels after vaccination, especially after the second mRNA dose. Two doses of either of the mRNA vaccines appears to push antibody levels even higher than natural infection.

Despite strong antibody production after vaccination, reports of breakthrough infections are still occurring. Emergence of SARS-CoV-2 variants, particularly the Delta variant, sometimes allow the virus to escape vaccine immunity. Delta is also more transmissible than previous variants, as evident in its rapid overtaking of other variants in all sequenced SARS-CoV-2 samples.

Fortunately, vaccines appear to reduce disease severity when breakthrough infections do occur (1, 2, 3).

While the focus has been on vaccination, there are many people who recovered from the virus. The CDC estimates 101 million symptomatic COVID-19 infections and 767,00 deaths have occurred in the USA. That leaves an estimated 100 million people that have beat the virus, the majority of whom have natural immunity (3, 4).

Studies on SARS-CoV-2 natural immunity show durable protection against reinfection. Some data even suggests that natural immunity is more protective than the vaccines (5, 6, 7, 8). When reinfection does occur, it also appears less severe than first infections (9).

Breakthrough infections display how difficult it is to produce a vaccine that fully protects against SARS-CoV-2. This difficulty means we must consider the difference between natural immunity and vaccine immunity, and what that means for SARS-CoV-2 as we move away from a pandemic emergency. To understand those differences in immunity, you must first understand some biology.

[caption id="attachment_192609" align="aligncenter" width="1920"] Doctor performs COVID-19 PCR test.[/caption]

PROTEINS, ANTIBODIES AND VARIANT BACKGROUND.

[caption id="attachment_192612" align="aligncenter" width="963"] Protein and subunits. Taken from InVivo Biotech website. Source: “Peptides vs Proteins - Peptide Information” (peptidesciences.com).[/caption]

The SARS-CoV-2 genome codes for 5 proteins: Nucleocapsid (N), Spike (S), Hemagglutinin esterase (He), Membrane (M) and Envelope (E). The virus uses Spike to bind to the human ACE2 receptor, which is a protein on the surface of human respiratory cells. If the S protein cannot bind to the human ACE2 receptor, then the virus cannot get into human cells. If the virus cannot get into human cells, then an infection does not occur. Therefore, due to the necessity of S to cause an infection, S is the SARS-CoV-2 protein targeted by the Pfizer, Moderna, and J&J vaccines.

While a natural infection will expose you to the whole virus, the vaccines only expose you to a part...

Proteins are a chain of amino acids. When the different COVID-19 variants are discussed, the implied variation is in the S amino acid sequence. This is because changes in the S amino acid sequence can change the virus's ability to bind to the ACE2 receptor, which in turn, can change the ability of the virus to cause an infection. In fact, the CDC does not even mention the other four SARS-CoV-2 proteins on its variant webpage.

Spike is about 1,273 amino acids in length. Full length proteins can be broken into smaller pieces called peptides, which are generally defined as a chain of 2 to 50 amino acids. By looking at these smaller protein pieces, we can examine vaccine and natural immunity at a lower level of detail, and get a better understanding of how these two types of immunity differ.

SARS-CoV-2 variants have differences at the level of individual S protein amino acids. For example, the Delta variant has around 13 amino acid changes in S compared to the original SARS-CoV-2 strain from Wuhan, China (the original strain is called the wild type variant). Thus, some, but not all, Spike peptides will have changed amino acid sequences.

[caption id="attachment_192613" align="aligncenter" width="987"] SARS-CoV-2 Variant Amino Acid Changes. Source: American Society for Microbiology. “How Dangerous Is the Delta Variant (B.1.617.2)?” (asm.org).[/caption]

Antibodies, which are large, Y-shaped proteins generated by your body's immune system to identify and neutralize foreign objects such as viruses, bind to 5-15 amino acid sequences called epitopes. A full-length protein such as S will have many potential epitopes. After infection or vaccination, the immune system creates distinct antibodies against many epitopes. The COVID-19 vaccines are designed to specifically target the portion of the virus’s S protein that binds the ACE2 receptor on human cells—Intuitively, this portion of the S protein is named the receptor binding domain (RBD).

Because antibodies are specific to an amino acid sequence, Delta’s 13 amino acid changes can inhibit antibody binding. This inhibition will sometimes allow the variant to escape from antibody binding, rendering antibodies that target those epitopes ineffective at neutralizing that strain of SARS-CoV-2.

The S protein’s RBD contains enough amino acids to trigger antibody production against multiple epitopes. But the RBD is not the only piece of S that induces an immune response, nor is it the only SARS-CoV-2 protein that our immune system targets.

This is critical: while a natural infection will expose you to the whole virus, the vaccines only expose you to a part—in this case the vaccine manufacturers targeted the portion of S protein that maximizes the chances of disabling the virus. That difference in starting material creates the potential for differential immune responses between those who have vaccine immunity, and those who have natural immunity.

[caption id="attachment_192608" align="aligncenter" width="1920"] COVID-19 vaccine.[/caption]

CURE-HUB ANTIBODY SIGNATURE DATA

Recently, we published an article at Cure-Hub that contains comprehensive vaccine and natural infection antibody signatures. To compare the two immune events, we examined antibody binding to 12-amino acid long peptides, that in sum, span the full length S protein. We also assessed antibody binding to the other SARS-CoV-2 proteins. To our knowledge, our article contains one of the most comprehensive COVID-19 antibody signatures available.

Our results showed about what you would expect. Vaccines induce a strong antibody response against the part of SARS-CoV-2’s S protein found in the vaccine, but natural infection tends to produce antibodies against a greater number of unique S peptides. For example, if we rank study participants by the number of unique S peptides with an antibody response, the top 3 people had a natural infection.

The most significant difference is antibody production against the virus’s nucleocapsid protein (N). This protein is not a part of the vaccines, so vaccinated individuals did not generate N antibodies. However, each naturally infected person we tested showed significant N antibody production. Our observation is also reported elsewhere in the scientific literature.

Vaccines produce fewer unique antibodies, which are all directed against the viruses S protein. That gives the virus a greater chance to escape antibody protection than natural immunity. This is because the virus can escape vaccine immunity by only mutating its S protein. Whereas to escape natural immunity, the virus needs to mutate both the S and N protein. The broader antibody responses after natural infection explains natural immunity’s greater protection from a mechanistic perspective.

One of the important aspects of antibodies that target N, is that N has a much slower mutation rate than S. This further reduces the risk for reinfection in naturally immune individuals.

When variants arise, they usually escape from some, but not all antibodies produced after a vaccine. This is how breakthrough infections occur. Most people may not even notice the breakthrough infection. In those that do have a symptomatic breakthrough infection, the majority will experience less severe illness. This is because of the remaining partial immune protection.

People with natural immunity have more comprehensive immune protection. A reinfection should be even less severe than a breakthrough infection. Once most people have natural immunity it will be more difficult to transmit the virus. Emergence of variants should also slow.

One of the most important metrics to follow, but not being reported by the American CDC, is population level N antibodies. This is because N antibodies are an indication of natural infection. If we see a rise in N antibodies while S antibodies are at near 100% from the vaccines, then it is evidence everyone will eventually get COVID-19.

[caption id="attachment_192607" align="aligncenter" width="1920"] Frontline workers test drivers for COVID-19.[/caption]

 SARS-CoV-2 THE ENDEMIC VIRUS

We are now at over 200 million globally distributed SARS-CoV-2 cases, many of which are in countries with low vaccination rates. This suggests the virus is now globally endemic, meaning the virus has become a permanent fixture in the environment. It is unclear how long natural immunity lasts in an endemic SARS-CoV-2 setting. Perhaps the long-term trajectory for SARS-CoV-2 is like that of the other endemic coronaviruses, such as HKU1 and OC43—in other words, a mostly benign, annoying yearly infection.

The vaccines carry risks, and a core concept in medicine is to do no more intervention than is necessary.

What does all of this mean going forward? It appears that each of us may one day get COVID-19, even with vaccine protection. This of course raises important questions about the COVID-19 vaccines. At Cure-Hub, our position is the vaccines do induce a strong immune response against their target. They save lives, and this is clear in the lower death rate associated with the Delta variant wave.

The existence of the Delta variant is evidence that the vaccine target is now changing, however, which leads to breakthrough infections. Despite those breakthrough infections, the vaccine does reduce infection severity. This makes vaccination very important in high-risk groups, such as elderly, and those with obesity, diabetes or cardiovascular disease.

There are legitimate concerns about the safety of the vaccines, and it is true that a subset of people have experienced adverse events (AEs) as a result of COVID-19 vaccination. However, besides age and gender, there have not been widely published reports on demographics, pre-existing immune signatures, or genetics in the few people who have vaccine related AEs. It is likely that people who react poorly are predisposed to a vaccine related complication. Meaning, AEs aren't just random. Data, down to the molecular level, needs to be explored to know more about who are having these adverse events and why.

The number of adverse cardiac events in young people, especially males, is high. The vaccine seems, in some cases, to be causing heart issues in some men under 29 years old (22-27 myocarditis events per million doses).

Due to the high COVID-19 survival rate in the under 29-year-old age cohort, it is reasonable to question the risk vs benefit of vaccination. This is especially true when not much is known about the vaccinated people who have cardiac events.

The apparent enhanced immune protection in naturally immune individuals also calls into question the necessity of vaccination in the cohort of 90-100 million previously infected people. The vaccines carry risks, and a core concept in medicine is to do no more intervention than is necessary. Without evidence of failed natural immunity after infection, the risks of vaccination may outweigh the benefits.

It is only a matter of time before the country finds consensus that SARS-CoV-2 is an endemic virus. Reaching that point is critical to evaluate our response during pandemic stages. We must take lessons in the biotech industry’s ability when regulatory reins are loosened, our minimal knowledge of a novel virus, the shortcomings of experts, and the value of freedom. So as we shift to our new understanding of SARS-CoV-2, it is a great opportunity to remind people that, in our free country, it is our responsibility to assess risk and protect ourselves as individuals.

The average American lifespan is 78.7 years. Parts of the USA have had 18-months of emergency lockdown orders (in one way or another). This means Americans have experienced reduced freedom to life, liberty, and pursuit of happiness for 2% of their expected lifespan. The proportion of life experienced under lockdown is much higher the lower in age you go. For example, 18 months represents 8.3% of an 18-year-old’s life.

At a certain point we must accept the tools to fight this virus are available to us all. Experts are helpful, but they do not have all the answers. Nobody knows you better than you know yourself. At Cure-Hub we recommend discussing the available tools to fight SARS-CoV-2 with your physician. They can help you decide what is best for you. Then it is up to each of us to decide how to act, while understanding that the freedom to make our own choice is the most important part of being American.

Stay safe and stay free.

Note: Cure-Hub LLC or Ian Martiszus do not recommend purposeful inoculation with SARS-CoV-2, or any virus for that matter. We wouldn’t even do that with a common cold.