How Worried Should We Be About the Variants?
DR. MICHAEL YEADON & MARC GIRARDOT
As the SARS-CoV-2 epidemic continues across the globe, many genetic modifications have started to appear in the virus. These are being sequenced, analysed1 and monitored by many scientists. This well known phenomenon occurs continuously for Influenza as well as for coronaviruses. Health authorities and mainstream media have been very wary of supposed heightened risk profiles of these new variants. They are also adamant about a potential risk of evasion from immunity, whether that immunity was acquired via infection or vaccination.
Some evolutionary virologists consider that viruses ‘attenuate’, or evolve towards less virulent forms. Some feel that novel pharmaceutical2 and non-pharmaceutical interventions3 – or specific circumstances4 – could possibly disrupt this evolutionary process and favour a more severe variant or threaten acquired immunity.
The recent downward trends5 in cases and in hospitalisations across the globe seem to indicate that the virus has probably not mutated in any way that would make it much more dangerous and that a healthy immune system is very capable of dealing with these new forms of the SARS-CoV-2 virus. Indeed, patients have been shown to recover naturally in most instances, just like they did from the original form of COVID-19.6 The paucity of confirmed re-infections with the virus, accompanied by clinical symptoms, despite hundreds of millions of infections over the last year,7 is consistent with a lack of ‘immune escape’.
Acquired immunity is fundamentally based on the recognition of a large series of three-dimensionally shaped protein markers called ‘epitopes’. These markers are formed from a virus’s genetic code. When a virus mutates, it can stop expressing some of these proteins, and, in principle, trump the immune arsenal specifically targeting these. And indeed, if all immunity against SARS-CoV-2 were based on one or two epitopes, and if those markers were to change, immunity would mechanically be broken.
But SARS-CoV-2 is a large virus8 with approximately 30,000 RNA bases (10,000 amino acids). Currently, the greatest difference between any ‘mutant variant’ and the original Wuhan sequence is limited to 26 nucleotide mutations.9 The genomic diversity of SARS-CoV-2 in circulation on different continents is fairly uniform.10 We know that the mutation rate in SARS-CoV-2 is slower than other RNA viruses because it benefits from a proofreading enzyme which limits potentially lethal copying errors.11 To date, these mutations have caused changes in less than 0.3% of the entire virus sequence. All variants are therefore currently 99.7% similar to the original Wuhan viral sequence.
To date, no robust scientific evidence proves that any of the variants identified are more transmissible or deadly than the original.12 By definition, variants are clinically identical. Once there is a clinical difference, then a new ‘strain’ of virus has emerged. Prior knowledge of viral mutation shows they usually evolve to become less deadly and more transmissible.13 This optimises their chance of spreading, as dead hosts tend not to spread viruses, and very ill hosts have reduced mobility and thus limit contact with others.14
Natural immunity to SARS-CoV-2 is gained in the immune system by the body ‘cutting up’ the virus into hundreds of pieces.15 Multiple pieces are used to develop a suitably diverse immune response to many parts of the virus. Specialised immune cells16 will launch an immune response if exposed to the same ‘learned’ viral fragment in the future. Prior immunity gained from the original SARS-CoV-2 should work perfectly well against any new ‘mutant variant’, given the 99.7% sequence similarity.17
The La Jolla Institute for Immunology recently published a paper which is a tour de force: a comprehensive assessment of the role played by thousands of linear protein epitopes in the SARS-CoV-2 protein sequences18 in acquired immunity. Reassuringly, the human immune system uses several hundred of the theoretically possible protein epitopes. Each individual uses a diverse selection of at least 18 epitopes to form their antibody repertoire (humoral immunity)19, 20 and a different, though overlapping, T cell repertoire targeting at minimum 30-40 epitopes (cellular immunity).21 This means that even if there are several changes in the virus’s RNA code and in its protein sequence, the majority of the epitopes will be unchanged. There is therefore no possibility that the human immune system will be fooled into regarding the variants as a new pathogen. Furthermore, even if a variant were to bypass some of the immune repertoire of an individual, this would be of no consequence for a population due to the diversity of repertoires. The authors themselves conclude: “This analysis should allay concerns over the potential for SARS-CoV-2 to escape T cell recognition by mutation of a few key viral epitopes.”
mRNA vaccines currently used for vaccination – Pfizer-BioNTech or Moderna – present the immune system with a large repertoire of targets, if not quite as large as a natural immune response. This is even more true of more traditional vaccines22 – Russia’s Sputnik and China’s Sinovac – which present an even wider repertoire.23 Given the breadth of immunisation and the relative independence of these immune responses, we believe that both humoral and cellular immunities will remain effective, even if one or several key immunological targets are erased.
Multiple confirming data points and experiments solidify this already robust scientific foundation: The prevalence of pre-existing immunity to SARS-CoV-2 found in multiple studies24,25,26 further validates our thinking, both for humoral immunity27,28 and cellular immunity.29 Many seem to have benefited from a form of immunity even though they had never met the actual virus, nor been vaccinated. These have gained their immunity from past epidemics and make up the large contingent of asymptomatics. The Tübingen University Hospital near Stuttgart, Germany found as much as 81% of its samples were carrying pre-existing specific T cells.30 Most likely, past common cold coronaviruses have – in effect – played an immunisation role against SARS-CoV-2. The same immunological mechanism has been proven to exist for influenza also.31
Some are advocating the vaccination of people who have recovered from COVID-19. Natural immunisation being the ultimate form of vaccination, we see absolutely no scientific nor medical justification for such a procedure. Even past infections by other forms of common cold coronaviruses have been found to protect from SARS-CoV-2. Injecting a vaccine should never be considered a trivial event. The decision should be based on a well thought out risk-benefit analysis. There is absolutely no patient benefit in vaccinating an immune person, only risks and possible unnecessary downsides32 such as fever.
The evidence above supports that immunity evasion – though a theoretical possibility – is very unlikely. Mutant variants, emerging overseas or domestically, are an inevitable biological reality once a virus is in the population. Closing international borders will not stop new mutations of the SARS-CoV-2 virus circulating in the population. It is a futile endeavour with no scientific basis.
Furthermore, immunity evasion may not be the most pressing issue with regards to COVID-19 and vaccine effectiveness. Could vaccines be partly ineffective for other reasons? Indeed, vaccines are different from drugs in that their mode of action is indirect.33 Vaccines rely entirely on a functional immune system. However, those suffering from severe forms of COVID-19 have predominantly been shown to be either very old and/or very sick with a weakened immune system.34 A recent survey from Yale University highlighted that blood samples taken from severe COVID-19 patients were lacking dendritic cells – a fundamental trigger of immune response – by a factor of between two and four.35 A deficiency in these signalling cells would thus significantly delay the immune response, giving the virus the opportunity to replicate exponentially, and present the immune system with a radically different context: a propagated virus and inflammation disseminated throughout the body. A vaccine’s mode of action would be subject to the same delay. Although vaccines could be helpful for patients with mildly deficient immune systems, they would most likely not save very old patients with advanced immune senescence. Thus overconfidence in vaccine effectiveness for the very old could be a major risk, and mitigation treatments and immune boosting strategies should instead be contemplated.36
Dr. Michael Yeadon
Scientific Board member of Panda
Expert in Allergy & Respiratory (A&R) Therapeutic/PhD in Biochemistry and Toxicology
Former Chief Scientific Officer at Pfizer A&R unit/CEO and Founder of Ziarco
25 years experience in Drug Discovery/40 Full Papers/63 Abstracts/two Books/six Patents
Member of Panda
Senior Advisor in Biotech & Automotive/INSEAD MBA
Advisor to an anti-Cancer therapeutic vaccine company/Ex-Global Lead of Cisco’s IBSG Automotive
30 years of experience in Industry, High Tech and Biotech/two Patents
1 GISAID: Global Initiative on Sharing Avian Influenza Data
2 “High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance” by A;K.Padhi, R;Shukla, P.Saudagar, T.Tripathi – iScience – March 22nd 2021
3 “The first three months of the COVID-19 epidemic: Epidemiological evidence for two separate strains of SARSCoV-2 viruses spreading and implications for prevention strategies – Two epidemics of COVID-19” by K.M. Wittkowski – April 29th 2020
4 “SARS-CoV-2 mink-associated variant strain – Denmark” by WHO – December 3rd 2020
5 “COVID infections drop 16% worldwide in one week: WHO” UN News February 17th 2021
6 “Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera” by A.Muik et al…– Science – January 29th 2021
7 “Infection fatality rate of COVID-19 inferred from seroprevalence data” by John P A Ioannidis – WHO – September 15th 2020
8 “SARS-CoV-2 (COVID-19) by the numbers” by Y.Bar-On, A.Flamholz, R.Phillips, R.Milo – eLife – April 2nd 2020
9 “USA/ME-HETL-J1539/2020 Clade 20G USA” by Matluk et al – November 19th 2020
10 “No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2”
11 “Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting” by Wai-Lung Ng et al… – Molecular Cell – September 3rd 2020
12 “No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2” by F.Balloux et al… – Nature – November 25th 2020
13 “We shouldn’t worry when a virus mutates during disease outbreaks” by Edward C. Holmes et al. – Nature Microbiology – February 18th 2020
14 “The Evolution and Emergence of RNA Viruses” by Edward C. Holmes – EID Journal – May 2010
15 “Immune responses to viruses” by British Society for Immunology
16 “Not just antibodies: B cells and T cells mediate immunity to COVID-19” by Rebecca J. Cox & Karl A. Brokstad – Nature – August 24th 2020
17 “Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351…” by Mehul S. Suthar et al. – PrePrint – February 22nd 2021
18 “Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases” by A.Tarke et al. – Cell – February 16th 2021
19 “SARS-CoV-2 and the Antibody Response in COVID-19 Patients” by Emily A. Teslow – Medical Affairs – August 2020
20 “Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity” by Ellen Shrock et al. – Science – November 27th 2020
21 “Comprehensive analysis of T cell immunodominance and immunoprevalence…” by A.Tarpe et al. – Cell – January 26th 2021
22 “Viral targets for vaccines against COVID-19” by L. Dai & G. F. Gao – Nat Rev Immunol – December 18th 2020
23 “Current vaccines under development and their major antigen targets” – Table 1
24 “Immunodominant T-cell epitopes from the SARS-CoV-2 spike antigen reveal robust pre-existing T-cell immunity in unexposed individuals” A. Nelde et al. – Nature Immunology – September 30th 2020
25 “SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls” by N. Le Bert et al. – Nature – July 15th 2020
26 “Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans” by J.Mateus et al. – Science – October 2nd 2020
27 “Pre existing and de novo humoral immunity to SARS-CoV-2 in humans” by Kevin W. Ng – Science – December 11th 2020
28 “Epitope-resolved profiling of the SARS-CoV-2 antibody response identifies cross-reactivity with endemic human coronaviruses” – Cell – January 19th 2021
29 “Immunodominant T-cell epitopes from the SARS-CoV-2 spike antigen reveal robust pre-existing T-cell immunity in unexposed individuals” by Swapnil Mahajan et al. – PrePrint – November 5th 2020
30 “SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition” by Juliane S. Walz – Nature – September 30th 2020
31 “Pre-existing immunity against swine-origin H1N1 influenza viruses in the general human population” by Jason A. Greenbaum et al. – PNAS – December 2009
32 “COVID-19 vaccine safety update” by the Advisory Committee on Immunization Practices (ACIP) – January 27th 2021
33 “How vaccines work” by publichealth.org
34 “Causes, consequences, and reversal of immune system aging” by E. Montecino-Rodriguez et al. – March 1st 2013
35 “Longitudinal analyses reveal immunological misfiring in severe COVID-19” Pr. A.Iwasaki – Nature – July 27th 2020
36 “Age-dependent immune response to the Biontech/Pfizer BNT162b2 COVID-19 vaccination” by Lisa Müller et al. – Preprint – March 3rd 2021
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