Why Natural Immunity Should (Must) Count

[UPDATED: September 26, 2021 to take into account data since the Delta variant became the predominant SARS-coV-2 strain in the US at the end of June 2021.]

The World Health Organization acknowledged in its scientific brief on COVID-19 Natural Immunity dated May 10, 2021 (1) that:

“Natural infection may provide similar protection against symptomatic disease as vaccination.”

It’s time for the Centers for Disease Control (CDC) to acknowledge the same.

It’s time to look at the scientific data showing that natural immunity from prior COVID-19 infection is not only as protective, but may actually be MORE protective than a vaccine, and that prior infection may also increase the risk for serious adverse vaccine reactions.

It’s time to make a science-based policy shift and rethink the CDC’s current recommendation that all eligible individuals should get a vaccine, regardless of whether they’ve already had COVID-19.

Antibodies, Memory B Cells, Memory T Cells & Long-Lived Plasma Cells

Immunity against most human coronaviruses that cause the common cold (hCoV-OC43, hCoV-229E, hCoV-NL63 and hCoV-HKU-1) may be short lived and not last longer than a year. (2)

But SARS-CoV-2 is NOT like most other human coronaviruses.

SARS-CoV-2, the human coronavirus that causes COVID-19, is much more closely related to MERS-CoV and SARS-CoV-1, which caused Middle East Respiratory Syndrome (MERS) in 2009 and Severe Acute Respiratory Syndrome (SARS) in 2003, respectively. In the case of MERS and SARS-CoV-1, antibodies have been detected years after initial infection, and immunity is thought to possibly be lifelong. (3,4,5)

90-99% of people who recover from COVID-19 develop detectable neutralizing antibodies. (1) SARS-Cov-2 antibodies from COVID-19 infection are detectable for at least 6-12 months after initial infection. (6,7,8) As time passes from the beginning of the pandemic, and antibodies in those with prior infection continue to be followed, we will likely see that antibodies endure long-term as they do for SARS and MERS.

And while SARS-CoV-2-specific IgG antibodies may wane over time, as is typical for most viral infections, this is not necessarily a sign of decreasing immunity. Increasing evidence (9,10,11,12,13,14,15) points to long-lasting B-cell and T-cell immunity and long-lived plasma cells after SARS-CoV-2 infection, even mild infection – which may confer lifelong immunity.

Memory lymphocytes produced after SARS-CoV-2 infection exhibit potent antiviral immunity. (12) When re-exposed to SARS-CoV-2 antigens, memory lymphocytes have multiple strategies to protect against reinfection. Memory CD4+ T cells secrete an antiviral cytokine, IFN-gamma. Memory CD8+ T cells can kill virus-infected cells directly. And memory B cells differentiate into IgG+ antibody-secreting plasmablasts. This memory immune response on re-exposure is capable of neutralizing the virus and preventing reinfection.

COVID-19 infection also induces lasting bone marrow plasma antibody protection. As antibody production wanes after initial infection, a small population of antibody-producing cells called “long-lived plasma cells” migrate to our bone marrow and continually secrete low levels of antibodies. Long-lived plasma cells were identified in patients with even mild COVID-19 disease, and the authors speculate that even asymptomatic people have long-term protection due to these long-lived plasma cells. (16)

Prior SARS-Cov-2 infection induces Memory B cell, Memory T cell and Long-lived Plasma Cell protection that confers LONG-TERM and possibly LIFELONG IMMUNITY.

Reinfection Rates are Very Low

In real life, reinfection rates are very low – even with the Delta variant. A study in Israel comparing those who were fully vaccinated with the Pfizer COVID-19 vaccine and those with prior infection during the period March 2020 – August 2021 found that vaccinated individuals without a history of prior infection had a a 6X to 13X risk INCREASED of a breakthrough COVID infection than unvaccinated individuals with natural immunity. The authors conclude that:

natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity.

https://www.medrxiv.org/content/10.1101/2021.08.24.21262415v1.full.pdf

While reinfection with SARS-CoV-2 can occur, six large studies from the US (17), UK (18), Denmark (19), Austria (20), Qatar (21), and US Marines (22), found that infection with SARS-CoV-2 provides 82-95% protection from reinfection for at least 7 months. (23,24)

Those with prior infection had at least 94% protection from symptomatic disease, rivaling the protection received after full COVID-19 vaccination. A retrospective Austrian study (20) of SARS-CoV-2 reinfection rates in 14,840 people with prior COVID-19 infection compared with the general population confirmed that prior infection provided 97% protection from hospitalization and 99% protection from death due to reinfection. The authors note that:

“Protection against SARS-CoV-2 after natural infection is comparable with the highest available estimates on vaccine efficacies. Further well-designed research on this issue is urgently needed for improving evidence-based decisions on public health measures and vaccination strategies.”

Natural Immunity is as Protective Against Variants as Vaccines

Recent studies have found that current global Variants of concern (VOCs) are unlikely to have an impact on CD4+ and CD8+ T cell immunity in both those with prior COVID infection and those who are vaccinated. Memory T-cell immunity from prior infection likely confers immunity against circulating variants, (25,26,27) even the Delta variant (B.1.617.2). (28)

With increasing reports worldwide of breakthrough infections after vaccination due to the Delta variant, it is imperative to understand the protective factors against serious hospitalization and death from Delta variant infections – whether it’s natural or vaccine immunity.

Natural Immunity May Be MORE Protective than Vaccines Against Current & Future Variants

Israel has seen a spike in recent COVID-19 infections due to the Delta variant in both vaccinated and unvaccinated individuals despite very high vaccination rates. Real-world data out from Israel since May 2021 revealed that natural infection was actually much more protective against new infection than vaccination. In fact, those with natural immunity from prior infection were 6.72 times less likely to get infected than those who only had immunity via vaccination. Of the 7,700 new cases of COVID-19 infection since May 2021, 3000 or about 40% were in vaccinated individuals, compared with only 72 or less than 1% in those with prior infection.

The Spike protein on the SARS-CoV-2 virus binds to receptors on human cells to allow the virus to invade, replicate and cause disease. The Spike protein has significant evolutionary pressure to mutate to allow easier entry into human cells. As a result, SARS-CoV-2 Variants of Concern have notable mutations in their Spike protein that increase transmissibility and infectivity.

While the Spike protein varies significantly across variants, the Nucleocapsid protein is surprisingly stable. Because it is encased in the virus, there is less evolutionary pressure for the Nucleocapsid protein to mutate than for the Spike protein.

The SARS-CoV-2 Nucleocapsid (N) protein (48 kDa) appears to be conserved across COVID-19 variants and does not mutate. (29)

The Nucleocapsid protein floats freely in the blood after it is released from infected cells and causes strong B-cell and T-cell immune responses. (30) Those with SARS-CoV-2 infection mount B-cell and T-cell responses against the SARS-CoV-2 Spike protein and Nucleocapsid protein, along with many other viral antigens.

On the other hand, current COVID-19 vaccines are designed to elicit B-cell and T-cell immune response against only the Spike protein of the SARS-CoV-2 virus. Concern has been raised that eventually enough mutations in the Spike protein may occur in new variants that vaccines targeting the SARS-CoV-2 Spike protein alone will lose their efficacy.

Because the Nucleocapsid protein does not seem to mutate in variants, Nucleocapsid B-cell and T-cell immunity may provide BETTER long-term protection from all current and future variants than a vaccine that only produces Spike protein immunity.

Because the SARS-CoV-2 Nucleocapsid protein does not mutate, the Nucleocapsid protein may be a better target for IgG antibody testing AND for future vaccine targeting.

Laboratories should include Nucleocapsid protein antibodies in serologic testing for prior SARS-CoV-2 infection. And vaccine manufacturers should investigate vaccines that induce immune response against the Nucleocapsid protein and other SARS-CoV-2 antigens, not just the Spike protein.

In addition, a meta-analysis (31) of 18 T-cell response studies to COVID-19 found that memory T cells from natural infection are effective against more than 1400 SARS-CoV-2 CD4+ and CD8+ epitopes. Epitopes are sites on the SARS-CoV-2 virus that T cells can recognize. Natural immunity confers broad T-cell response to the SARS-CoV-2 virus. Such broad T-cell response makes it difficult for SARS-CoV-2 variants to acquire enough mutations in its epitopes to “escape” the body’s immune response after prior infection. In contrast, rapid mutations in the Spike protein may allow for increased opportunities to “escape” the body’s immune response after vaccination.

Due to the broad immune response to SARS-COV-2 infection, enduring immunity from future variants is more likely with natural infection than vaccination.

With increasing reports of breakthrough infections due to the Delta variant in fully vaccinated individuals around the world, it is imperative to determine how protective vaccination truly is against not just getting seriously sick and dying from Delta infection, but also against contracting asymptomatic or mild/moderate disease and transmitting it to vulnerable populations, including children and the elderly who may not mount an adequate immune response even after full vaccination.

The CDC Must Change Its Definition of Vaccine Breakthrough Infections

The only way we will know how well prior infection or vaccination protects against clinical disease and the spread of the Delta variant is if the CDC changes its definition of vaccine breakthrough infections BACK to what it was before May 1, 2021.

According to the CDC, “As of May 1, 2021, CDC transitioned from monitoring all reported vaccine breakthrough cases to focus on identifying and investigating only hospitalized or fatal cases due to any cause. This shift will help maximize the quality of the data collected on cases of greatest clinical and public health importance.” (32)

The CDC’s changed definition of vaccine breakthrough infections is bad policy …

Breakthrough Delta variant infections, deaths and hospitalizations after vaccination are increasing, but the current definition cannot accurately reflect the true numbers.

As of July 19, 2021, the CDC reported 5,914 breakthrough infections with 5,601 hospitalizations and 1,141 deaths. On the other hand, at the end of April before the CDC changed its definition of breakthrough cases, the CDC had reported 2X the number of breakthrough cases, with 10,262 vaccine breakthrough infections, 10% of which resulted in hospitalization and 2% in death. Twenty-seven percent (27%) of these vaccine breakthrough infections were asymptomatic.(33), confirming the WHO’s observation that most breakthrough Delta variant infections are mild or asymptomatic. With the changed CDC definition, 88% of breakthrough infections noted at the end of April would not have been counted because they did not result in hospitalization or death.

Asymptomatic and mild-moderate infection with the Delta variant that do not result in hospitalization and death are increasingly being reported in the US and other countries. Vaccinated people can still get COVID-19 and transmit it to others. However, the CDC’s change in definition of vaccine breakthrough infections makes it impossible to understand how variants are spreading among vaccinated individuals, or how variants are spreading from vaccinated individuals to unvaccinated individuals, including children and others who remain vulnerable.

If we do not track asymptomatic and mild-moderate vaccine breakthrough infections, we will never know the answers to these very important questions:

• How effective is the vaccine in preventing infection and transmission, and how does this compare to those with natural immunity from past infection?
• Do vaccinated people with mild or asymptomatic breakthrough infections spread disease – especially the Delta variant and other Variants of Concern?
• Does vaccination contribute to milder symptoms (even from variants)?
• What role do variants play in vaccine breakthrough infections?
• Since children have such low rates of hospitalization and death from COVID-19 infection to begin with, how will we know if vaccinated children have breakthrough infections and spread disease?

Those with Prior Infection Do NOT Need a Vaccine

A large study (34) of over 52,000 employees of the Cleveland Clinic Health System found that while COVID-19 infections increased in those without a prior history of infection who remained unvaccinated, the rate of SARS-CoV-2 infection was essentially ZERO for:

• Unvaccinated people with history of prior infection
• Vaccinated people with history of prior infection
• Vaccinated people without history of prior infection

The authors conclude that:

“Individuals who have had SARS-CoV-2 infection are unlikely to benefit from COVID-19 vaccination, and vaccines can be safely prioritized to those who have not been infected before.”

Those with Prior Infection May Be at Higher Risk for Serious Adverse Events After a Vaccine

No study has yet proven that people with prior COVID-19 infection benefit from a vaccine.

On the other hand, prior COVID-19 infection has been linked with an increased risk of serious adverse events after vaccination.

• Prior infection may increase the risk for myocarditis in young males (35)
• The Moderna COVID-19 vaccine was associated with more frequent and severe side effects after the 1^st dose in those with prior infection (36)
• 1 in 3 people with prior infection report more systemic side effects vs. 1 in 5 without prior infection after the Pfizer COVID-19 vaccine (37)
• Prior COVID-19 infection is associated with increased adverse events after the Pfizer vaccine (38)
• A recent study found that prior SARS-COV-2 infection was associated with an almost 5X increased odds of clinically significant symptoms following dose 1.

Prior infection may be a risk factor for serious adverse vaccine events.

Higher risks for serious adverse vaccine reactions may be due to the higher immune response that those with prior infection mount after vaccination. This will be especially important to elucidate for children who are at very low risk for serious COVID-19 hospitalization and death. The Pfizer vaccine trial in 12-15 year olds found that children mount a 1.76X HIGHER antibody response to vaccination than 16-25 year olds. However, more is not always better. As we’ve seen with COVID-19 infection, a stronger immune response isn’t always optimal. Inflammation, when dysregulated, can lead to cytokine storm and sepsis with disease.

A stronger immune response to vaccination may increase the risk for short-term and long-term serious adverse vaccine events in children. Moreover, children with prior infection are expected to mount an even stronger immune response to vaccination even after the 1st dose, and may potentially be at even greater risk for post-vaccine serious adverse events.

As a small but increasing number of children are reported to have serious post-vaccine events including myocarditis/pericarditis, there is an immediate public health need to investigate whether prior infection is a risk factor so that we can know how to mitigate these risks. The risks for children after COVID-19 vaccination must be LOWER than the already very low risk of serious morbidity and mortality in children after COVID-19 infection.

Assessing whether prior infection is a risk factor in those who have had serious vaccine adverse events would be simple enough to do. Children who have experienced serious vaccine adverse events, including myocarditis/pericarditis, should be compared to children who have not experienced serious adverse vaccine events by measuring IgG antibody and T-cell responses to the Nucleocapsid protein of the SARS-CoV-2 virus. Immune responses to the Nucleocapsid antigen would only be present in those with prior infection. If prior infection does appear to be a significant risk factor for post-vaccine myocarditis/pericarditis and other serious adverse events, then this must be disclosed to parents and pediatricians, and the option to test for prior immunity must be available to all before vaccination. This very same must be assessed for adults as well.

If prior infection is identified as a risk factor for serious adverse vaccine events, individuals must have the option to test for prior infection before vaccination for a more accurate risk/benefit assessment in order to make a more informed decision.

How Do You Know if You’ve Had Prior Infection?

While those with prior positive SARS-CoV-2 PCR or rapid antigen test results may know that they have had prior infection, many with asymptomatic or mild past infection may not know their prior infection status. And many who experienced a flu-like illness in early 2020 before PCR testing was widely available are left to question whether that actually could have been COVID.

Unfortunately, as with rapid antigen and PCR testing for acute infections, current antibody and T-cell testing for past infection are currently authorized under Emergency Use Authorization guidelines, and do not necessarily have the sensitivity and specificity required to make individual and public health decisions with certainty.

A study (39) that followed SARS-CoV-2 Spike and Nucleocapsid antibodies in people with prior infection for 9 months found significant differences between testing using Abbott, Roche and DiaSorin assays. The authors note, “Our analysis confirms substantial differences in antibody persistence by assay, with the Abbott assay showing a marked decline both in antibody titres and seropositivity over a seven-months period. This finding implies that several serosurveys conducted globally with the Abbott assay … may underestimate [emphasis added] the true cumulative number of SARS-CoV-2 infections. Conversely, the antibodies detected by DiaSorin and Roche appear to remain at high levels for at least nine months.”

There are at least 19 different types of SARS-CoV-2 neutralizing antibodies produced by B-cells in COVID-19 patients. Most commercial labs test only for IgG antibodies against the S1 subunit of the Spike protein.  Some labs are beginning to test for antibodies against the S2 subunit of the Spike protein, Nucleocapsid protein and Receptor Binding Domain (RBD) protein. Research must be done to identify which neutralizing antibodies persist and may be better reflections of long-term natural immunity.

For COVID-19 infections that may have occurred in the distant past, T-Cell testing may be more accurate than IgG antibody testing to determine immunity. T-Detect (40) offers T-Cell testing for individuals 18 years and up.  IGeneX (41) may be the most accurate option at the moment for both antibody and T-cell testing for all ages. IGeneX uses recombinant ImmunoBlot technology to detect antibodies against 4 SARS-CoV-2 antigens (S1, S2, Nucleocapsid, and RBD).  Unfortunately, neither of these tests are inexpensive and will not be accessible to many.

Accurate, accessible, and affordable antibody and T-cell testing MUST be a public health priority.

The FDA and CDC Must Accept SARS-CoV-2 antibody and T-cell Testing as Proof of Immunity

The FDA’s statement on May 19, 2021 (42) that “results from currently authorized SARS-CoV-2 antibody tests should not be used to evaluate a person’s level of immunity or protection from COVID-19 at any time, and especially after the person received a COVID-19 vaccination” makes no scientific sense. Antibodies are accepted as proof that vaccines provide immunity in the trials upon which the FDA has granted Emergency Use Authorization. Antibodies must also be accepted as proof that prior infection provides immunity.

It makes no scientific or common sense that antibodies are not considered valid assessments of immunity to COVID-19 – whether due to prior infection or vaccination.

Because children rarely have serious enough COVID-19 disease to result in hospitalization or death, the FDA has accepted “immunobridging” to infer effectiveness of COVID-19 vaccines in children. The primary endpoint to prove efficacy in pediatric vaccine trials is to show that children produce as many antibodies, and not fewer than, those produced by 16-25 year olds after vaccination. The primary endpoint is NOT to show that COVID-19 vaccines prevent hospitalizations and deaths in children. If antibody titers are acceptable as proof that vaccines provide immunity, they must also be acceptable as proof that prior infection provides immunity.

In fact, assessing antibody titers after the 1st dose of a vaccine to identify those who have mounted a sufficient immune response and do not need a 2nd dose may reduce the risk of those serious adverse vaccine reactions that are almost exclusively seen after Dose 2 – like myocarditis/pericarditis in children and young adults.

Those with Prior Infection Should be Considered Immune

I am not recommending that individuals purposefully get COVID-19 infection to develop immunity.

But I AM urging the CDC to change its recommendation that children and adults with a history of prior COVID-19 infection should still get a COVID-19 vaccine.

Those who have had prior COVID-19 infection or have been fully vaccinated should all be considered IMMUNE.

Children and adults who have had prior COVID-19 infection should no longer live in fear that they are at risk for re-infection or for infecting others.

A CDC Policy Shift Could Reduce Serious Adverse Vaccine Events

The CDC must change its guidance and state that those with prior COVID-19 infection do NOT need a vaccine.

The CDC must make a science-based shift in policy, and prioritize vaccines for those who have no evidence of prior infection. Without a shift in policy, those with prior infection may sustain avoidable, serious, and potentially life-changing adverse vaccine events.

The risks for children after COVID-19 vaccination must be lower than the already very low risk of serious morbidity and mortality in children after COVID-19 infection. We must do everything we can to identify which children are at risk for serious adverse reactions and death after COVID-19 vaccination. As of September 16, 2021, over 5.5 million children in the US have had COVID-19 infection, (43), which is likely a significant undercount given that asymptomatic infection is common in children. If children with prior infection are at increased risk for serious adverse events after vaccination, and already have long-term natural immunity precluding the need for a vaccine, this science-based shift in policy could prevent 5.5 million children from having the chance of developing post-vaccine complications like myocarditis.

A CDC Policy Shift Could Help End the Global Pandemic

This science-based shift in policy will allow the over 44 million US children and adults who have already had COVID-19 to re-enter society safely and confidently, knowing they are as immune, if not more immune, than those who have been vaccinated..

This science-based shift in policy will allow much needed vaccine doses to be ethically distributed from the US to the many countries that are still feeling the devastating impact of the pandemic and get vaccines to vulnerable individuals who need protection the most.

As of September 26, 2021, there have been 42,770,371 reported cases of COVID-19 in the US with 684,884 deaths. (44) This means over 42 million children and adults in the US have had COVID-19 and survived. And this number may actually be significantly higher with estimates in Nature Research that by the end of 2020, 31% of the US population had been infected with SARS-CoV-2 – with only 22% confirmed by testing and over 75% with undocumented infections,

If the CDC makes this evidence-based policy shift, there could be over 84 million doses of vaccine that are available to distribute to countries in need. The US already has millions of unused COVID-19 vaccine doses that are set to expire and go to waste in a matter of weeks to months. Out of the nearly 394 million vaccine doses that have been delivered to vaccine partner sites across the US, a little over 340 million doses have been administered. (45). That’s over 53 million vaccine doses that will go to waste unless the US makes plans to redistribute them immediately to countries in need.

A global pandemic will not end without a united global effort.

A global pandemic will not end without a rational, science-based approach …

References:

1. https://apps.who.int/iris/bitstream/handle/10665/341241/WHO-2019-nCoV-Sci-Brief-Natural-immunity-2021.1-eng.pdf
2. http://www.nature.com/articles/s41591-020-1083-1
3. http://www.nature.com/articles/s41467-020-18450-4
4. http://medrxiv.org/lookup/doi/10.1101/2020.02.12.20021386
5. https://wwwnc.cdc.gov/eid/article/27/5/20-4056_article
6. https://www.medrxiv.org/content/10.1101/2021.04.27.21256207v1
7. https://www.cell.com/immunity/pdf/S1074-7613(20)30445-3.pdf
8. https://journals.asm.org/doi/10.1128/mbio.01991-20
9. https://journals.asm.org/doi/10.1128/mbio.01991-20
10. https://journals.asm.org/doi/10.1128/mbio.01991-20
11. https://www.nature.com/articles/s41591-020-01143-2
12. https://www.medrxiv.org/content/10.1101/2020.08.11.20171843v2
13. https://www.biorxiv.org/content/10.1101/2020.11.01.362319v1
14. https://www.biorxiv.org/content/10.1101/2020.11.15.383323v1
15. https://science.sciencemag.org/content/371/6529/eabf4063
16. https://www.nature.com/articles/s41586-021-03647-4_reference.pdf
17. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2776810 
18. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00675-9/fulltext
19. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00575-4/fulltext
20. https://pubmed.ncbi.nlm.nih.gov/33583018/

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