Wow these slides are packed with information and accompanying citations - truly a great resource for anyone following the literature regarding COVID-19 and especially the variants of concern.

I need more time to digest this presentation, but there are two important topics that I feel are missing or at least underrepresented:

1) The effectiveness of early outpatient treatment using a combination of existing medicines (antibiotics, corticosteroids, antiplatelet/antithrombotic) [0a] [0b]

2) The risk of vaccine induced immune escape

Regarding 2) The basic idea is that imperfect vaccines may cause selective pressure which further enhances the fitness of highly virulent pathogens. This may be particularly relevant to the widely deployed mRNA vaccines, which induce an immune response that is highly targeted towards the SARS-CoV-2 spike protein.

Here are some peer reviewed publications on the topic, along with a few excerpts [1][2][3][4][5][6]. To be clear, the excerpts I'm providing below do not contradict any of the major points from the presentation. However, I do hope they illustrate that there is another important dimension to discuss when evaluating the evolutionary dynamics of SARS-CoV-2.

Excerpts from [1]:

- "A growing body of evidence suggests that the targets of several human vaccines are evolving"

- "For example, resistance to influenza and herpes-virus drugs emerged within a few years of FDA approval, and resistance to antivirals rapidly arises within human immunodeficiency virus (HIV) and hepatitis C virus (HCV)-infected patients"

- "The best documented example of vaccine resistance evolution occurred in Marek’s disease, a commercially important disease of chickens caused by Marek’s disease virus (Gallid herpesvirus II). There, two generations of vaccines were undermined by viral evolution. Those vaccines prevented disease, but even before the pathogen evolved, they did not prevent viral infection, replication, or transmission. Instead, Marek’s disease virus reached large population sizes even within vaccinated hosts and was able to transmit to new hosts. As a result, the virus was likely able to generate genetic diversity within vaccinated hosts, and vaccine-induced selection was able to act during transmission between hosts. The benefits of prophylaxis were thus missing."

Excerpts from [2]:

- "Here we show experimentally that immunization of chickens against Marek's disease virus enhances the fitness of more virulent strains, making it possible for hyperpathogenic strains to transmit. Immunity elicited by direct vaccination or by maternal vaccination prolongs host survival but does not prevent infection, viral replication or transmission, thus extending the infectious periods of strains otherwise too lethal to persist. Our data show that anti-disease vaccines that do not prevent transmission can create conditions that promote the emergence of pathogen strains that cause more severe disease in unvaccinated hosts."

Excerpts from [3]:

- "The spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the molecular target for many vaccines and antibody-based prophylactics aimed at bringing COVID-19 under control."

- "Such a narrow molecular focus raises the specter of viral immune evasion as a potential failure mode for these biomedical interventions. With the emergence of new strains of SARS-CoV-2 with altered transmissibility and immune evasion potential, a critical question is this: how easily can the virus escape neutralizing antibodies (nAbs) targeting the spike RBD?"

- "Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection."

- "Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities"

- "The speed at which nAb resistance develops in the population increases substantially as the number of infected individuals increases, suggesting that complementary strategies to prevent SARS-CoV-2 transmission that exert specific pressure on other proteins (e.g., antiviral prophylactics) or that do not exert a specific selective pressure on the virus (e.g., high-efficiency air filtration, masking, ultraviolet air purification) are key to reducing the risk of immune escape"

Excerpts from [4]:

- "... evidence for vaccine-induced disease evolution is mounting for many diseases ..."

- "... vaccines can reduce parasite fitness by preventing infection, reducing within-host growth, or preventing transmission. These have been shown to have very different evolutionary consequences for parasite virulence evolution"

- "Vaccines which reduce within-host growth rates are predicted to increase virulence"

- "Infection with multiple strains of the same parasite can result from separate infection events of co-circulating strains, or because the parasite has a rapid mutation rate and generates strain diversity through mutation within the host. Biologically, distinctions between ‘types’ of multiple infection matter because they affect the relatedness of the co-infecting parasites and relatedness can influence the optimal virulence strategy for the parasite"

[0a] Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection (2020)
https://www.amjmed.com/article/S0002-9343(20)30673-2/fulltex...

[0b] Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19) (2020)
https://scholarlycommons.henryford.com/cgi/viewcontent.cgi?a...

[1] Why does drug resistance readily evolve but vaccine resistance does not? (2017)
https://royalsocietypublishing.org/doi/pdf/10.1098/rspb.2016...

[2] Imperfect Vaccination Can Enhance the Transmission of Highly Virulent Pathogens (2015)
https://journals.plos.org/plosbiology/article?id=10.1371%2Fj...

[3] Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein (April 2021)
https://pubmed.ncbi.nlm.nih.gov/33909660/

[4] The adaptive evolution of virulence: a review of theoretical predictions and empirical tests (2015)
https://www.cambridge.org/core/services/aop-cambridge-core/c...

[5] The phylogenomics of evolving virus virulence (2018)
https://www.nature.com/articles/s41576-018-0055-5

[6] Monitor for COVID-19 vaccine resistance evolution during clinical trials (Nov 2020)
https://journals.plos.org/plosbiology/article?id=10.1371/jou...