Dec 26, 2021

SARS-CoV-2 Origins, Immunology, and Treatments. Here’s What We Really Know About “The Science™” (PART III) - OMICRON edition

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Since late November, rapid transmission of the Omicron variant (B.1.529) across the globe sparked another wave of hysteria beginning. Concern that the available vaccines would lose efficacy against this heavily mutated strain cast a foreboding shadow on the holiday season, and government agencies predicted a dismal winter of death for the unvaccinated. Exacerbated by macabre statements from heads of state (the White House made a foreboding remark uncomfortably reminiscent of that Game of Thrones one-liner, “Winter is Coming…”), COVID madness rocked the financial world as countries waffled over lockdowns and social distancing measures. Although it is unequivocal that Omicron has spread faster than any other variant of concern to-date (representing over 73% of all new cases in the US alone), this alarming statistic has obscured one, simple question… “should we even care?

The answer, as it turns out, is not really.

In Part I of this series we discussed the basics of immunology, the structure and pathophysiology of the SARS-CoV-2 virus, and controversy surrounding the origins of the virus (lab grown or natural evolution?).

In Part II of this series we discussed the evolution of the pandemic, government response, scientific principles of social distancing, and the COVID-ian cult of vaccine zealots.

In Part III, we will discuss:

Background

Omicron was first reported to the WHO from South Africa on November 24, 2021, from a specimen collected on November 9th. Within one week it had spread to the United States and Europe, and is now confirmed in 20 other countries. Epidemiologists have estimated the pandemic’s new growth rate (R) to have doubled from when the Delta variant was predominant, hinting at Omicron’s increased transmissibility and ability to evade the immune system [1]. The rate of transmission is only one epidemiologically relevant variable, second in importance to the more medically relevant statistics of severe disease (hospitalizations) and deaths. Not a single country with documented Omicron cases has a new death rate equal to, or greater than, the new case rate. In fact, South Africa, the United States, the United Kingdom, and Denmark all have plateauing or declining death rates. Omicron may be spreading like wildfire, but it appears to be about as dangerous as a diamond strike matchstick.

Omicron new cases and deaths in South Africa (26% fully vaccinated), the United States (61% fully vaccinated), the United Kingdom (70% fully vaccinated), and Denmark (78% fully vaccinated)

Let’s get a few facts straight. Omicron has quickly become the dominant variant across the globe and death rates have consistently declined over the last month. Does this mean that Omicron is statistically less deadly than previous variants of concern (most notoriously, the Delta variant)? Possibly, but severity data is confounded by other variables such as previous infection (i.e., a significant portion of the population has already been infected, boosting their immunity to new strains) and the age and overall health of those infected (i.e., Omicron is preferentially spreading among the young and healthy, those more likely to recover [2]). Regardless, this is a positive deviation from that pandemic’s trajectory and could signal the transition of the pandemic to an endemic, in which we restore a semblance of normalcy in the presence of the virus, assisted by yearly boosters and the recently approved Pfizer and Merck anti-COVID pills.

Pfizer and Moderna have released preliminary laboratory data demonstrating that a third (booster) dose of their mRNA vaccines significantly increase neutralizing antibody titers against the Omicron variant. While this molecular indicator of vaccine efficacy is informative, the real test is how the booster vaccines reduce the probability of contracting the Omicron variant over time (since it is well-established that protection begins to wane significantly within 4-6 months of the second shot [3]). A large-scale clinical observation of patients in England (21,271 Omicron cases, 351,287 Delta cases) found the current vaccines much less effective at targeting Omicron compared to the Delta variant, a 2-dose regimen of the Pfizer vaccine offering a mere 20% of the protection it provides against Delta. What about those previously infected with past variants? The same study concluded that previous infection offers 19% protection against Omicron, roughly the same amount as two doses of the Pfizer vaccine [2]. Research at Columbia University further supports Omicron’s strong resistance to neutralization by antibodies collected from both previously infected (also known as “convalescent”) and vaccinated individuals, identifying four specific mutations in Omicron’s spike (S) protein that confer greater antibody resistance [4] . Detailed investigation into Omicron’s acquired mutations paints a complex picture of gain of function and immune evasion [5]. The reasons for the loss of vaccine and antibody efficacy will be dissected in this article.

Immune Escape

Acquired mutations

The exponential growth in new coronavirus cases is a testament to Omicron’s ability to evade the immunity acquired by previous infection or derived from vaccination. Where did this ability come from? Omicron has acquired 37 amino acid substitutions (see schematic below), meaning mutations have occurred at 37 different locations within the virus’s genetic code that alter the structure and function of the virus. This is more than three times as many mutations as acquired by Delta. Fifteen of Omicron’s mutations occur within the receptor-binding domain (RBD) of the spike (S) protein (bold in the table below), which is critical for viral infection via binding the ACE2 receptor on the surface of human bronchial (airway) and lung cells [5].

A short-sighted strategy

The current vaccines all target the S-protein by instructing the immune system to create neutralizing antibodies that block S-protein-mediated binding to the ACE2 receptor, thereby neutralizing viral entry into host cells (hence the name, “neutralizing antibodies”). Predictably, this myopic focus on the S protein at the expense of investigating other viral protein targets (namely the  membrane, envelope, and nucleocapsid proteins [6]) has led severe reduction in vaccine efficacy due to loss in antibody affinity for Omicron’s heavily mutated S-protein.

3-dimensional depiction of SARS-CoV-2 S protein. SARS-CoV-2 S in fully open conformation (PDB: 7K4N) with positions of mutated residues in Omicron highlighted on one protomer in green or red spheres in or outside the ACE2 footprint (ACE2), respectively.

In addition to decreasing the effectiveness of vaccines, these mutations have been implicated in Omicron’s apparent replication advantage over Delta, the significant reduction in activity by monoclonal antibody therapies, and the significant reduction in neutralization by polyclonal antibodies found in the (convalescent) blood plasma of individuals with prior infection. In a recent study, nearly three months prior to the identification of the Omicron variant, researchers engineered a synthetic SARS-CoV-2 pseudotype containing an S-protein with 20 amino acid mutations that possessed nearly complete resistance to the polyclonal neutralizing antibodies generated by individuals with prior infection or who did not receive an mRNA vaccine. This resistance was mitigated by convalescent plasma from previously infected individuals who also received an mRNA vaccine, suggesting that booster shots may retain efficacy as more people recover from the virus and continue to get vaccinated [7].

Transmissibility

An analysis of 208,947 Delta cases and 15,087 Omicron revealed an exponential growth rate estimate of 0.45/day – 0.34/day, representing a 1.5 – 2.3 day doubling time, compared to 7-14 days for Delta [2]. The cause of Omicron’s accelerated spread is likely due to its increased affinity for the ACE2 receptor in human bronchi and lungs.

A study conducted by researchers at The University of Hong Kong (HKUMed) found that Omicron infects and multiplies 70x faster than both the Delta variant and original SARS-CoV-2 virus in the human bronchus (the tube that carries air from the trachea to the lungs). Importantly, Omicron infection in the lung was found to be significantly lower than the Delta and original virus, indicating a lower severity of disease. Taken together, this evidence suggests that Omicron rapidly infects and multiplies in the bronchi but spares the lung cells, allowing people to incubate the virus to high concentrations with mild symptoms, encouraging its spread as they continue about their daily lives [8].

The degree of infectivity in the bronchial tissue is regulated by how tightly Omicron’s S protein binds to the ACE2 receptor. Cameroni et al. showed that Omicron’s affinity for the human ACE2 receptor is approximately 2.4x that of the original SARS-CoV-2 virus. Interestingly, the Alpha variant has a whopping 6.2x increase in affinity, yet the spread of Alpha was not nearly as aggressive as Omicron [5]. Clearly, there is more than receptor affinity to the story. The researchers also found that Omicron’s S-protein can bind the ACE2 receptors of mice, a phenomenon not observed in the original, alpha, and beta variants.  This finding supports the theory that reverse zoonotic transmission (i.e., the transmission of the virus from animal to human, back to animal, and finally back to human) may be the way that the virus mutated so heavily. This theory is further supported by another study, in which researchers found that four of the mutations in a mouse-adapted SARS-CoV-2 virus, Q498R, N501Y, K417N, and Q493R, were also found in the Omicron variant. N501Y is known to increase affinity for the ACE2 receptor, and Q493R is thought to be the cause of the cross-species affinity between Omicron and the mouse ACE2 receptor [9].

Vaccine Efficacy

Determining vaccine efficacy is relatively straightforward, and relies on measuring molecular indicators of immune function, such as neutralizing antibody activity, and epidemiological meaningful metrics, such as the relative probability of contracting the virus at multiple timepoints post-vaccination (hazard ratio) or the probability of developing severe disease over time (odds ratio). New research is being published daily. Here’s a summary of some of the findings.

Neutralizing antibody activity

A joint research project between researchers in the United States and China concluded that Omicron is resistant to neutralization by convalescent plasma (i.e., the antibodies in the blood plasma of previously infected and fully recovered individuals) as well as from individuals vaccinated with one of the “Big Four” (Pfizer-BioNTech, Moderna, AstraZeneca, and J&J). Decreases in IC50 neutralization activity of convalescent plasma (as measured by the increase in the antibody concentration needed to reduce viral infection by 50%) were as great as 32-fold between Omicron and D614G (a common mutation found in all the variants of concern). Similarly, decreases in neutralization activity of antibodies found in the plasma of vaccinated individuals were as great as 21-fold and 8.6-fold for the Pfizer and Moderna mRNA vaccines, respectively. A third (booster) shot of Pfizer or Moderna reduced the fold reduction to 6.5x. Neutralization by the AstraZeneca and J&J adenovirus-based vaccines examined was below the lower limit of detection of the assay [4].

Neutralization of D614G and B.1.1.529 (Omicron) by convalescent and vaccine plasma

A joint effort between the United States and various European institutions confirmed a severe reduction in plasma neutralizing activity between Omicron and past variants for both vaccinated and convalescent patients. Individuals vaccinated with the Moderna, Pfizer, or AstraZeneca vaccines experienced a 33-, 44-, and 36-fold reduction in neutralizing antibody activity, respectively [5].

Neutralization of Omicron SARS-CoV-2 pseudovirus by plasma from COVID-19 convalescent and vaccinated individuals

Researchers at the Imperial College London developed an immunological model to capture the relationship between neutralizing antibody titers (NAT) in vaccine-induced and infection-induced protection. They estimated that the Pfizer vaccine NAT was reduced by 4.5x compared to the Delta variant, which predicts a drop in vaccine efficacy in severe disease from 96.5% (against Delta) to 80.1% (against Omicron) at 60 days post-booster (assuming that NAT decay is at the same rate following boosting as is it for the primary 2-dose course). The results look slightly better if the NAT decay is assumed to be half of the decay rate for the primary course, resulting in 85.9% protection against Omicron [10] .

A high-throughput screen of naturally occurring, neutralizing antibodies generated by previously infected (CoV-1 and CoV-2) and vaccinated individuals revealed 247 endogenous antibodies that bind to the Receptor Binding Domain (RBD) of the S-protein. Researchers clustered the antibodies into six groups based upon the similarities in the epitopes (the specific regions of the RBD) that they bind and found that single amino acid mutations in the S-protein could impair binding of diverse epitope groups. Over 85% of the tested neutralizing antibodies were escaped by Omicron, although two epitope groups that exhibit broad sarbecovirus activity were less affected by Omicron [11].  This information could play a crucial role in developing new monoclonal neutralizing antibody therapies.

Epidemiological relevance

The “Hazard Ratio” (HR) is a metric commonly used by epidemiologists to quantify the outcome of anti-viral trials. The HR for a vaccine is the probability that a vaccinated individual will contract the virus divided by the probability that an unvaccinated individual will contract the virus, at that same point in time, divided by the time interval. Vaccine Efficacy (VE) can be estimated by VE = 1- HR, therefore a high HR indicates that a vaccine is unlikely to be effective. Ferguson et al. concluded that VE against Omicron waned significantly in patients treated with both 2 and 3-dose regimens of the AstraZeneca and Pfizer vaccines, with relative Hazard Ratios (i.e., the ratio of Omicron’s HR to Delta’s HR) increasing from 1.86 to 4.32 and 2.68 to 4.07 in the AstraZeneca group and Pfizer group, respectively. VE for Omicron can be calculated using the relative Hazard Ratio and VE for the Delta variant, using the following formula: VE(Omicron) = 1-HR(Omicron)[1-VE(Delta)]

Depending on the Delta VE estimate, researchers compute vaccine efficacy estimates of 0-20% and 55-80% for 2-dose and 3-doses, respectively (i.e., two doses of the Pfizer vaccine yielded up to 20% of the protection it gives against the Delta variant) [2].

Monoclonal Antibody Evasion

To date, the FDA has authorized eight different monoclonal antibody therapies to treat SARS-CoV-2 infection. Monoclonal antibodies (mAbs) are laboratory-synthesized proteins that target very specific regions of the virus (called “epitopes”) and neutralize the virus by interfering with its binding to the ACE2 receptor on human bronchial and lung cells, or by binding to other viral surface proteins to encourage immune system clearance.

Approved mAbs include:

  • Tixagevimab co-packaged with cilgavimab, is authorized for pre-exposure prophylaxis of COVID-19 in immunocompromised patients (the only antibody treatment administered pre-infection) (EUA issued December 8, 2021, latest update December 20, 2021)
  • Casirivimab and imdevimab, administered together (EUA issued November 21, 2020, latest update November 17, 2021)
  • Bamlanivimab and etesevimab, administered together (EUA issued February 9, 2021, latest update December 3, 2021)
  • Sotrovimab (EUA issued May 26, 2021, latest update December 16, 2021)
  • Tocilizumab (EUA issued June, 24 2021)

Monoclonal antibodies developed to neutralize SARS-CoV-2 activity can be divided into two classes based on the regions of the virus that they target. Seven out of the eight approved mAbs target the S-protein and block viral entry via the ACE2 receptor. It has been shown that combining two ACE2 receptor blocking mAbs confers greater resistance to viral variants that contain mutations to the Receptor Binding Domain of the S-protein. The second class of mAbs is represented by sotrovimab, which does not target ACE2 receptor binding. In a study examining the efficacy of these commercially available monoclonal antibodies in neutralizing Omicron infectivity, it was determined that most mAbs were completely ineffective against the Omicron variant. Some, such as sotrovimab, S2K146, and S2X324 retained neutralizing activity, but at a significant reduction (~200-fold). This implicates the heavily mutated S-protein as Omicron’s vehicle for immune escape [5].

Neutralization of Omicron SARS-CoV-2 pseudovirus by clinical-stage monoclonal antibodies

The authors also tested a larger panel of 36 neutralizing mAbs targeting either the N-terminal domain (NTD) or 3 specific regions within the Receptor Binding Domain (RBD) of the S-protein. They found that several of these mAbs are effective at neutralizing multiple SARS-CoV-2 variants, confirming that antibodies that target multiple conserved epitopes can result in protection against future variants.

An independent group performed similar neutralization studies using an Omicron pseudovirus and 19 well-characterized monoclonal antibodies against the S-protein, 17 of which directly target the Receptor Binding Domain (RBD) and 2 targeted to the N-terminal domain (NTD). In agreement with the results published by other groups, the 17-antibody cluster was severely impaired, with these mAbs targeting the RBD losing >100-fold potency. This reduced efficacy was not relegated to the mAbs targeting the RBD exclusively, as the 2 mAbs targeting the NTD also showed substantial declines in activity. Notably, all 4 mAbs used in the clinic lost significant neutralization activity against Omicron [4].

Resistance of Omicron to neutralization by a panel of 19 monoclonal antibodies targeting both the RBD and NTD of the S-protein

Should We Even Worry?

“What’s a Magneto?”

The word “mutation” sounds dangerous. Popularized by fictional works ranging from the Marvel Universe to zombie thrillers, “mutant” generally refers to a genetically altered organism with freakish abilities. Sometimes conjured in a lab, and other times a fantastical product of evolution gone wrong, our collective understanding of mutation immediately draws parallels between the pandemic and movies like Outbreak (1995), Contagion (2011), and 28 Days Later (2002). The truth is that organisms, and their cellular building blocks, are constantly mutating without any malicious intent. The cells in your body are dividing imperfectly, replicating your genetic code with small errors strewn throughout. The “science” promulgated by the media is that the virus will continue to mutate and necessarily become more dangerous; and End of Days scenario in which the virus cannot be contained and kills everything it touches. The logical inconsistencies are obvious even to a non-scientist. Think about it, if the virus is so deadly that it kills its host within hours of infection, then how would it spread? Clearly, a virus that seeks to reach pandemic levels must keep its host alive long enough to replicate and spread throughout the population. There’s a reason that Ebola did not leave Africa and decimate the Western World – Ebola virus disease had a fatality rate of 50%. There is a difference between virulence (i.e., how deadly a virus is) and transmissibility (i.e., how quickly a virus spreads).

Mutations by the minute

SARS-CoV-2 is classified as an RNA virus, relying on the error-prone RNA polymerase to replicate its genetic substrate (in this case, RNA, instead of DNA). Replication cycles occur on the order of hours, guaranteeing that a genetically diverse virus population exists within a host at any point in time. Not all mutants are fit for survival, and natural selection removes those virions that lack replication efficiency (as defined by the number of virions that are produced per unit of time) or high transmissibility (the ease with which the virus transmits from person to person, commonly defined by R). It is possible that a virus acquires mutations that improve both its replication efficiency and virulence, but that is not a given. Predicting the course of viral evolution is not possible, but that has not stopped the media from speculating wildly about the “superbugs” that are inevitably going to ravage the world.

Stating the obvious

Back to the question… should we even worry about Omicron? Let me just leave this here.

Cases are on the rise and deaths are steadily declining. Does this necessarily mean that Omicron is not dangerous? No. There are other confounding factors such as better access to therapies, such as monoclonal antibodies and anti-viral pills, and the simple fact that most of the global population has achieved 19-80% protection from Omicron by having previously been infected, vaccinated at least once, or both. Regardless, in the context of today’s world, Omicron is not wreaking the kind of havoc that warrants lockdowns, forced vaccination, and hyper-stringent social distancing policies. It is not worthy of the time, attention, and negative press it is receiving. If anything, we should be overjoyed that an impotent variant is the dominant force of the pandemic.

Feel-good statistics

So far, most of the discussion regarding Omicron’s severity has been anecdotal. Early reports from clinicians in South Africa described Omicron’s symptoms as similar to the common cold. As the data has come in, it is becoming clear that there is a significant reduction in risk of hospitalization for Omicron cases in the UK, Denmark, Scotland, and South Africa. In a study conducted by the Imperial College of London, clinicians found that there was a relative reduction in risk of hospitalization for Omicron compared to Delta of 20-25%, when using attendance at a hospital as the endpoint, and 40-45% when using a hospital stay of one day or longer as the endpoint [12]. In a preprint publication titled “Early assessment of the clinical severity of the SARS-CoV-2 Omicron variant in South Africa,” researchers calculated the odds ratio of requiring hospitalization relative to Delta to be 0.2 (95% CI 0.2-0.5), implying that there is an 80% reduction in risk of hospitalization due to Omicron compared to Delta. However, once hospitalized, there was no difference in the odds of contracting severe disease between Omicron and Delta infected patients. Interestingly, Omicron-infected patients did have a reduced risk compared to earlier Delta-infected patients, possibly due to the higher population immunity as the pandemic has unfolded  (adjusted odds ratio 0.3, 95% CI 0.2-0.5) [13]. By all accounts, Omicron is significantly less severe than Delta.

Protection by prior infection?

We have already discussed how antibodies from previously infected patients who subsequently received a mRNA vaccine were able to neutralize a synthetic SARS-CoV-2 spike protein [7], and how neutralizing antibody activity in convalescent plasma alone is severely inhibited [4]. But what does this mean in a “real-world” context? Investigators at the Imperial College of London published an analysis on the risk of reinfection by Omicron in patients who successfully recovered. They found the relative risk of reinfection to have risen from 0.15 with Delta to 0.81 with Omicron, representing a 5.4x increase in reinfection risk. This suggests that prior infection provides 19% of the protection to Omicron as conferred by previous infection by Delta. Taken together, the research suggests that previous infection certainly offers some benefits, which are optimized by receiving a single booster dose.

Big Pharma Response

Both Pfizer and Moderna have released preliminary data on their vaccine efficacy against the Omicron variant. Pfizer announced (December 8, 2021) that three doses of its mRNA vaccine (BNT162b2) produced significant neutralization titers, while two doses proved ineffective by this metric. The data also indicates the 25-fold increase in antibody titer by three doses v. two doses is comparable to the antibody titers observed after two doses against the original strain, which we know is associated with high levels of protection. Interestingly, 80% of the epitopes in the S-protein were recognized by killer (CD8+) T cells, which may mean that even two doses offers durable immunity against severe disease. Pfizer plans on continuing to develop an Omicron-specific vaccine (available by March 2022), and promises to deliver 4B total vaccine doses in 2022.

“Although two doses of the vaccine may still offer protection against severe disease caused by the Omicron strain, it’s clear from these preliminary data that protection is improved with a third dose of our vaccine. Ensuring as many people as possible are fully vaccinated with the first two dose series and a booster remains the best course of action to prevent the spread of COVID-19.”
~ Albert Bourla, Chairman and Chief Executive Officer, Pfizer
“Our preliminary, first dataset indicate that a third dose could still offer a sufficient level of protection from disease of any severity caused by the Omicron variant. Broad vaccination and booster campaigns around the world could help us to better protect people everywhere and to get through the winter season. We continue to work on an adapted vaccine which, we believe, will help to induce a high level of protection against Omicron-induced COVID-19 disease as well as a prolonged protection compared to the current vaccine.”
~ Ugur Sahin, M.D., CEO and Co-Founder of BioNTech

Moderna announced (December 20, 2021) that a 50ug booster (half the dose of the primary course) increases Omicron neutralizing antibody levels by 37-fold, and a 100ug booster increases levels 83-fold. The company will continue to develop an Omicron-specific booster (mRNA-1273.529) and is testing its current booster (mRNA-1273) doses in ongoing Phase 2/3 studies of approximately 300-60 patients per arm. The company already announced the safety and tolerability data from the Phase 2/3 study of 100ug booster, and the systemic adverse events were limited to those seen after the primary two-dose series.

“The dramatic increase in COVID-19 cases from the Omicron variant is concerning to all. However, these data showing that the currently authorized Moderna COVID-19 booster can boost neutralizing antibody levels 37-fold higher than pre-boost levels are reassuring. To respond to this highly transmissible variant, Moderna will continue to rapidly advance an Omicron-specific booster candidate into clinical testing in case it becomes necessary in the future. We will also continue to generate and share data across our booster strategies with public health authorities to help them make evidence-based decisions on the best vaccination strategies against SARS-CoV-2.”
~ Stéphane Bancel, Chief Executive Officer of Moderna

Moderna also announced that it is already studying two muti-valent boosters designed to anticipate mutations such as those found in the Omicron variant. The company appears to be creating S-protein variants that contain mutations conserved across the Beta and Delta variants (a strategy that we will discuss at the end of this article).

Universal vaccine

S-protein mania

To date, all the focus has been on characterizing the vaccines’ ability to induce a strong neutralizing antibody response against the S-protein. This effort is lacking in two major ways: First, vaccine manufacturers have failed to quantify the effect on the cellular component of the immune system, namely T cell-mediated immunity [Learn more about the components of the immune system here]. This is extremely important, as antibody-mediated immunity is transient in nature, but T cell-mediated immunity is durable, lasting months to years [14], [15]. Secondly, the vaccines only expose the immune system to a very specific region (Receptor Binding Domain) of just one surface protein – the Spike protein. The SARS-CoV-2 virus contains other surface proteins (nucleocapsid, N; membrane, M; and envelope, E) that are immunogenic, and infection with the live virus induces a more robust response against these other targets. This is important because the Receptor Binding Domain of the S-protein is the most highly variable region across variants, while the N and M proteins are known to be very well conserved (i.e., unchanging) between variants [16].

Some early work by academic groups has been done to investigate the T cell response to vaccines. In an observational study of 36 healthy people who had no history of COVID and 11 who had previously recovered, researchers found that the first dose of mRNA vaccine elicited a strong helper T cell response, which predicted the strength of neutralizing antibody and killer T cell activity. The killer T cell levels were boosted after a second dose of the vaccine. Comparatively, both helper and killer T cell levels were high in the 11 recovered patients before they received a mRNA vaccine. These levels were not substantially changed after vaccination [17]. The authors concluded that a double dose of mRNA vaccine elicits the same T cell response as prior infection, which is understood to offer long-lasting immunity (years). This is great news but does not solve the problem of the highly-mutagenic (i.e., rapidly mutating) S-protein. The reduction in vaccine efficacy is attributed to this phenomenon.

“For people who haven’t had COVID-19, the first dose powerfully primes the pump, and the second dose turns on the whole engine—but having had COVID-19 is like having had that first vaccine dose already. It is important to point out, however, that a complete understanding of the relative importance of these T cell responses, compared to antibody, in protection from future infections will require larger clinical studies.”
~ E. John Wherry, PhD, chair of the department of Systems Pharmacology and Translational Therapeutics and director of the Penn Institute of Immunology in the Perelman School of Medicine at the University of Pennsylvania

Perhaps the solution to a universal vaccine is in the well-conserved nucleocapsid (N) and membrane (M) proteins? A recent investigation into the viral proteins recognized antibodies primed by prior infection found that most of the patients presented a specific immune response against the N-protein, and to a lesser extent the RBD of the S-protein [18]. Researchers have shown that the N-protein plays a key role in incorporating the viral RNA into its progeny and in the protein replication complexes that synthesize the CoV-2 RNA prior to viral budding [19]. Taken together, the N-protein may be a suitable target for a universal vaccine capable of providing protection against future variants.

Other research has demonstrated the production of antibodies targeted against two epitopes of the M-protein, showing similar immunoreactivity as the S- and N-proteins during the acute stages of infection. Anti-M antibodies persisted after the patients recovered (i.e., the convalescent phase of infection) [20]. Clearly, the immune response to live SRS-CoV-2 infection is more robust than that of S-protein vaccination, and the “vaccine escape” phenomenon witnessed by the Omicron variant is due to the obsession with the S-protein.

Pan-coronavirus vaccine

A vaccine with broad-spectrum efficacy against all the known sarbecovirus strains (including SARS-CoV-1 and SARS-CoV-2), and high likelihood of protection against theoretical (“pre-emergent”) mutations, is the Holy Grail. Recently, scientists discovered that people who survived infection by the 2003 SARS-CoV-1 virus and also received the Pfizer SARS-CoV-2 vaccine (BTN162b2) were better protected against the variants of concern than healthy patients who received the Pfizer vaccine. Importantly, the serum from these “dual-clade” patients contained high levels of neutralizing antibodies against all 10 SARS viruses tested, including several that only occur in animals but may be capable of zoonotic transmission. The researchers concluded that these high levels of neutralizing antibodies against a broad range of SARS viruses found in the convalescent plasma of SARS-CoV-1 survivors suggest that a combination of CoV-1 and CoV-2 vaccines may be able to elicit broad immunity against the entire group of sarbecoviruses [21].

Perhaps the key to durable immunity is to administer a SARS-CoV-1 booster in patients who already received their Pfizer/Moderna/J&J vaccines? BioVaxys certainly thinks so. The company intends to leverage its haptenized viral protein vaccine platform to induce immunity against all or most sarbecoviruses by immunizing people who have convalesced (i.e., recovered) from a documented Covid-19 infection, or received a full course of any Covid-19 vaccine recognized by the World Health Organization, with a novel vaccine composed of the dinitrophenyl ("DNP")-modified S-spike protein of SARS-CoV-1. [Read press release here]

"Scientists dream of a pan-Coronavirus vaccine that would protect the population against any SARS-like respiratory virus that might mutate and emerge from a wild animal in the future. Our approach could constitute a pan-sarbecovirus vaccine that would protect humans against a very dangerous subgroup of Coronavirus that could emerge from the wild and cause as much devastation as Covid-19."
~ Dr. David Berd, Chief Medical Officer of BioVaxys
"There have been over 217 million recoveries following confirmed cases of Covid-19 (www.statista.com) and 6.6B  doses have been given of Covid-19 vaccine (Bloomberg Oct 15 2021); this total target population of almost 4 billion people represents a massive commercial opportunity for proposed our pan-sarbecovirus booster vaccine, which has the potential to confer cross-reactive neutralizing antibodies, not only against all Covid-19 variants, but future emerging dangerous zoonotic sarbecoviruses."
~ James Passin, Biovaxys Chief Executive Officer

How can we get ahead of the variants?

Perhaps a pan-coronavirus vaccine is not possible, but maybe we can use Big Data to predict with some degree of certainty how the virus might mutate in the future, and what protein targets might make for robust vaccines? Predictive bioinformatics may allow us to forecast how SARS-CoV-2 may mutate in the future. The field of epitope mapping and epitope prediction has made significant strides since it was first developed in 1981. In principle, it is possible to predict what regions of the viral proteins antibodies and T cells will recognize, estimate their antigenicity, and compare epitope clusters across SARS-CoV-2 variants. Based on the mutation sites of past SARS-CoV-2 variants, we may be able to predict which amino acid substitutions are likely to take place in the future.

A potential strategy might look like this:

  1. Sequence the S- and N- genes of all the variants. These sequences will produce a peptide library. Peptides are pieces of a protein and are composed of amino acids.
  2. Using epitope mapping, identify the S- and N- peptides (8 to 11 amino acids in length) that are likely to induce an immune response (cytotoxic T cell activation). One might employ BioVaxys's technique of haptenization to increase the immune response to the selected peptides.
  3. Cluster the peptides based on sequence overlap and select the clusters that are well-conserved across SARS-CoV-2 variants.
  4. Identify the mutation sites within each cluster that map to past variants.
  5. Produce combinatorial peptide vaccines using epitope clusters from both the N- and S- proteins. Engineer these peptides to contain combinations of known mutations.

The genius is in limiting the size of the possible solution set (i.e., the number mutations). One strategy may be to infer how a mutation will affect viral replication and transmission, and eliminate mutations that are obviously deleterious. We already know some gain-of-function mutations, such as the N501Y mutations that increases affinity for the ACE2 receptor, and Q493R is thought to be the cause of the cross-species affinity between Omicron and the mouse ACE2 receptor. This is a good starting point to begin the investigation.

References

[1] Callaway, E., & Ledford, H. (2021, December 02). How bad is Omicron? What scientists know so far. [Link]

[2] Report 49 - Growth, population distribution and immune escape of Omicron in England. (n.d.). [Link]

[3] Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study [Link]

[4] Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2 [Link]

[5] Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift [Link]

[6] Viral targets for vaccines against COVID-19 [Link]

[7] High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape [Link]

[8] HKUMed finds Omicron SARS-CoV-2 can infect faster and better than Delta in human bronchus but with less severe infection in lung [Link]

[9] But Mouse, you are not alone: On some severe acute respiratory syndrome coronavirus 2 variants infecting mice [Link]

[10] Report 48: The value of vaccine booster doses to mitigate the global impact of the Omicron SARS-CoV-2 variant [Link]

[11] B.1.1.529 escapes the majority of SARS-CoV-2 neutralizing antibodies of diverse epitopes [Link]

[12] Report 50 - Hospitalisation risk for Omicron cases in England [Link]

[13] Early assessment of the clinical severity of the SARS-CoV-2 Omicron variant in South Africa [Link]

[14] Robust SARS-CoV-2-specific T cell immunity is maintained at 6 months following primary infection [Link]

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[17] Penn Study Details Robust T-Cell Response to mRNA COVID-19 Vaccines—a More Durable Source of Protection [Link]

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