SARS-CoV-2 Thoughts

As SAGE implied in their 20th Technical Update's note 1.8.1 , we have effectively multiple serotypes of SARS-CoV-2 already, as Delta antisera doesn't neutralize B.1.351 nor B.1.621 virus meaningfully. That makes South Africa a potentially interesting case, because B.1.351 and C.1.2 emerged there. B.1.621 emerged in Colombia and has accounted for a significant percentage of cases, but Delta caused a serious wave in only South Africa. Beta was never recorded in Colombia and Delta barely touched them, and interestingly, they are now far below their record high infections, indicating that B.1.621 antisera is effective against its respective virus. https://origin-coronavirus.jhu.edu/region/colombia The lack of Delta's emergence could be geographic and political, but it may also mean that B.1.621 antisera is effective against Delta, which would be very encouraging news. https://outbreak.info/situation-reports?pango=B.1.621&selected=COL&loc=IND&loc=ZAF...

Vaccinated people infected by Delta are more likely to be hospitalized than unvaccinated people by Alpha. The statistical power of this study isn't great, but it implies that vaccinated people are more likely to need hospitalization. Ware the confounders. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00475-8/fulltext Reading the full paper, we find 1.9% of unvaccinated Alpha infectees required hospital admission. 2.2% of unvaccinated versus 2.3% of vaccinated Delta infectees required it, and 3.4% of vaccinated Alpha infectees required it. Thus, strangely, vaccination appears in these findings to increase the risk of hospitalization or emergency treatment required. The statistical power of these findings isn't very great because of too few hospital admissions amongst vaccinated infectees, and bear in mind we vaccinated people at higher underlying risk first and more thoroughly and the propensity of people who have been vaccinated to also be more l...

Original antigenic sin(OAS) has not yet been demonstrated in SARS-CoV-2 . However, I strongly believe that OAS will manifest itself, and it will be a bad and worsening problem over time. If I am correct, it may mean that getting vaccinated will become actively dangerous, depending on antibody-dependent enhancement(ADE) and its degree. OAS occurs when an immune response is produced by the body to a closely related pathogen or vaccine(such as a different strain of a virus) instead of generation of a novel immune response . This is because of homology between the two intruders' epitopes and resulting cross-reactive immune activity. SARS-CoV-2 has clearly demonstrated induction of variably cross-reactive antibodies with strain-variable neutralization potential. It has been demonstrated in many viruses ranging from Dengue Fever to influenza to HIV-1 . The set of viruses is not arbitrary: OAS abuse is a particularly effective strategy in viruses that mutate quickly, like influe...

Summary: The "efficacy" of a vaccine(VE) is a convenient number, but it's often provided without vital context that would ensure it is interpreted correctly. There are different kinds of efficacy that matter, and the numbers reported are often at peak levels following vaccination. It is in the commercial, professional, and political interest of drugmakers, the media, virologists, and policymakers to emphasize the highest number to demonstrate the power of the vaccines. The 3 primary outcomes that vaccination is intended to prevent are severe disease, infection, and transmission. The number for severe disease is likely to be highest, while the number for transmission is likely to be lowest. This is because different aspects of the immune response affect each. There are 3 main takeaways: VE is usually reported in terms of prevention of severe disease, VE can change against infection and severe disease independently, and SARS-CoV-2 is likely to escape from today...

SARS-CoV-2 is known to be a seasonal virus because the amount of viral transmission depends critically on the temperature . There are higher loads of viral inoculum that are transmitted greater distances when it's cold and absolute humidity is lower, and people are more likely to gather inside together for warmth. https://www.frontiersin.org/articles/10.3389/fpubh.2021.650493/full This is true of all strains, and we are entering autumn with a higher case count than we had last year. Also, last winter, Alpha was dominant nearly entirely alone, and it's not antigenically very distant from the original S protein. Instead, today, we now have many antigenically distant strains and variants of concern(VoCs). Check the dot plot for cross-immunoreactivity between strains in the following article. https://www.sciencemag.org/news/2021/08/new-sars-cov-2-variants-have-changed-pandemic-what-will-virus-do-next Through those two factors, we should see new domestic highs in case co...

SARS-CoV-2 caught most experts off guard with its evolutionary alacrity , but it always should have been expected to be very good at evolution despite a relatively low mutation rate . The progenitor virus(or, at least, the majority of its genome) came from bats. Bats have amazing immune systems due to their colony lifestyle in cramped quarters and their high metabolic rate. Further, coronaviruses have the longest genomes of any known +ssRNA viral family, and viruses are under constant evolutionary pressure to keep their genomes small. The genome of SARS-CoV-2 is about 30kb in length. The value of the genome was evidently great enough to compensate for that pressure. There is more highly conserved genetic material in coronaviruses than others, which in SARS-CoV-2's case means a lot of finely tunable accessory genes that screw up the immune system badly and even vicious microRNA's outside the coding regions of actual genes . SARS-CoV-2 has absolutely ingenious replicatio...

The Delta strain of SARS-CoV-2 has a longer asymptomatic period than earlier strains: around a day more. This is because it becomes detectable by PCR in 1.5 fewer days than previous strains, on average, but that is slightly counterweighted by faster symptom onset. Thus, although overall, symptoms present themselves slightly more quickly than in other strains, this still allows for longer aymptomatic transmission. https://www.nature.com/articles/d41586-021-02259-2 Although these mutations probably just generally facilitate spread, they demonstrate that the virus has the ability to adapt itself to our quarantine strategies. SARS-CoV-2 has now demonstrated that it can modify both of these timepoints -- seroconversion and symptom onset -- independently, and it can probably modify each timepoint in either direction. It's not clear just how long it can make its incubation or asymptomatic phases, though, because extension of that time could come at the cost of pathogenicity over...

Masks, in an ideal setting, produce an immense reduction in the amount of virus that passes through them, on the order of 98-99%. https://pubmed.ncbi.nlm.nih.gov/33441205/ The major issues are people not wearing them properly and people wearing poor ones, which didn't matter much early in the pandemic, where surgical or even cloth masks sufficed. https://pubmed.ncbi.nlm.nih.gov/32673300/ More infectious strains change the calculus because either a smaller number of virions is sufficient for infection or there are just more virions being expelled, and masks are a percentage reduction. A population educated on how to do a proper fit test with an N95 (or KN95) mask should see a dramatic decrease in transmission even with Alpha or Delta, although preliminary data out of Israel, where masking is mandatory indoors and outdoors, indicates that compliance or proper masking is not comprehensive or that surgical masks might not be effective enough anymore. Here is a great review ...

https://github.com/cov-lineages/pango-designation/issues/188 This was always to be expected as Delta encountered a larger, more densely vaccinated population, but it's still happening with remarkable speed. There is still no change in the RBD, as I had predicted, but S:L5F is unique. It's in the signal sequence for the S protein and thought to increase viral secretion further. It is a part of B.1.526(Iota). https://europepmc.org/article/PPR/PPR180476 https://outbreak.info/situation-reports?muts=S%3AL5F Most of the others are in the S2 subunit, indicating that Delta is taking full advantage of P681R and syncytia. N1074S appears to be becoming fixed, and it had appeared in no lineage before B.1.617.2. Its increased viability is almost certainly tied to P681R given its position in the S2 subunit. https://outbreak.info/situation-reports?muts=S%3AN1074S Q613H never appeared in a really dominant A or B strain, but it was theorized to have worked in roughly the same ...

Why am I COVID-19 vaccine resistant? I believe the current versions of SARS-CoV-2 vaccines are poor, and it was always inevitable that they would become poor because of slow global vaccination rates and a use of a single, highly mutable gene, S, which makes escape easier. https://www.sciencemag.org/news/2021/08/grim-warning-israel-vaccination-blunts-does-not-defeat-delta Further, they will probably only get worse given the rate of evolution in SARS-CoV-2 today. That rate is likely to only accelerate unless we get R below 1 for all strains, which is nearly impossible if we're starting from R0's around 8 . There looms the spectre of antibody-dependent enhancement(ADE), which is a property of other betacoronaviruses. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943455/ I think other vaccines hold better promise and will not need to be administered nearly as frequently because they target other parts of the immune system or virus, and their safety profi...

Initially, SARS-CoV-2's focus was on improved infectiousness.  However, as the virus continues to spread, that may become less relatively important, unless it were antigenically drifting enough, in which case the focus would remain on transmissivity.  But we're seeing trends in isolates that immune escape is becoming relatively more important.  That may abruptly flip if sufficient antigenic drift occurs or the virus somehow evolves the ability to evade antibodies created against it well enough..  This will be particularly true if it exhibits better ADE through mutations. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC7943455/ Anyway, with more antibodies from vaccination and natural infection accumulating but sufficient escape from them to mutate, the virus will want to start working on the adaptive immune response so that it can reside in the body longer for better transmission, especially with its ability to form syncytia and the rapid mutation that occurs...

P681R appears better than P681H in Delta, and the other way around in Alpha. That could be a false signal from a founder effect, but after this much time and selective pressure, I seriously doubt it.  It's the other residues for Delta and Alpha that are most interesting, because P681H alone in Alpha does little and Delta stinks with H681 or P681. https://www.biorxiv.org/ content/10.1101/2021.03.08. 434499v1.full https://outbreak.info/ situation-reports?pango=B.1.1. 7&muts=S%3AP681R https://outbreak.info/ situation-reports?pango=B.1.1. 7&muts=S%3AP681H https://outbreak.info/ situation-reports?pango=B.1. 617.2&muts=S%3AP681H https://outbreak.info/ situation-reports?pango=B.1. 617.2&muts=S%3AP681R This paper reports that Alpha with H681(GISAID accession EPI_ISL_999340) is more infectious than Delta with P681.  Delta with R681 obviously dominated.  Alpha's RBD has 200x the binding affinity for hACE2 as compared to Delta's RBD. Unfortunately, they did ...

In support of my conclusions, observe that Mexico, Central America, and the north of South America are seeing healthy co-circulation of VOC's that are antigenically distant.  Delta is not stomping out these VOC's; it is at about 50% prevalence there, and has little representation in the rest of South America.  B.1.621, Kappa(B.1.617.1, which has a markedly different S protein than B.1.617.2), and P.1.x are growing steadily.  Mexico has just set a record for new weekly and monthly cases. Delta took over in the US much more quickly and thoroughly, probably because we had much lower prevalence of the other strains than they did at the beginning(B.1.621 emerged in Colombia) and more import from overseas, even though we're more vaccinated(Mexico is at 22% fully vaccinated).  We might expect even greater expansion of those strains here over time.  You can watch the relative percentage of sequenced strains since Delta's export by zooming the map and press...

  I'd like to detail exactly why I think Dr. Gottlieb's prediction is off, but not entirely wrong, and what strains I think may be faced this winter.  His premise that Delta spreads so rapidly that it will eventually burn itself out, perhaps even before winter, is very plausible and even likely.  Note that summers will favor strains with better transmissibility, while winter will favor strains with better immune evasion, due to inoculum levels varying with temperature. It's the idea that cross-reactivity to anti-Delta antibodies will confer broad resistance to other strains, and thus the end of the pandemic, that I disagree with. Depending on how fast Delta mutates relative to how fast it spreads, it may not even be a progenitor of the next major strain.  I would say the odds depend on recombination and the localization of existing mutations.  If its increased transmissibility is due mostly to its increased viral load in the nasal passages, it is l...

  I have the utmost respect for Dr. Gottlieb and have appreciated his prescience on many issues.  He's called a lot of the pandemic better than most.  However, I don't think this will be one of his better predictions; he got a little unlucky in his timing, as his comments were before SAGE's findings.  Based on them, I'm siding with Larry Brilliant here. https://www.cnbc.com/2021/08/ 09/dr-scott-gottlieb-says-the- covid-delta-surge-may-be-the- final-wave-in-us.html https://www.cnbc.com/2021/08/ 09/covid-epidemiologist-larry- brilliant-on-delta-variant- vaccinations.html That is because infection with Delta will confer limited immunity in both space and time to variants of the K417N/T/E484Q/K/N501Y sort.  These variants generally don't have great transmission dynamics, but with a completely different antigenic presentation than B.1.617.2.x, they don't need to.  They just need to be good enough to spread on their own, as they are effectively not eve...

The inability of Delta serum to protect against Beta/B.1.621 virus indicates that, as SAGE predicted, sufficient antigenic drift has occurred since the beginning of the pandemic such that only a bivalent vaccine can provide protection today. This is not surprising when considering that the two strains took qualitatively different paths towards immune evasion.  Delta increased the distance between two beta sheets in the RBD by 1.5 angstroms, making the energy required for antibodies to inactivate the virus greater.  Beta and B.1.621 directly modified their epitopes and relied on electrostatic, hydrophobic, or other properties to make the antibodies unable to bind.  We do not know how many other qualitatively different paths there are out there, but it's safe to assume, "a lot." This means we can't just amp up the immunogenicity of the vaccine to compensate for the evolution of the virus.  It must be bivalent as of today.  We will try to find a new t...