COVID-19

SARS-CoV-2 Update

It’s time for our next 14-day moving average determinations for SARS-CoV-2 for the United States and my thoughts on vaccines, SARS-CoV-2 therapeutic agents and mutant viruses. We use the WORLDOMETERS aggregators data set to make any projections since it includes data from the Department of Veterans Affairs, the U.S. Military, federal prisons and the Navajo Nation.

SARS-CoV-2 infections per day have been increasing in the United States for 4 consecutive weeks despite underreporting by states and the failure to capture positive home tests and a decreased screening program in most states. The number of infections per day in the United States has increased by 59.7% in the last 2 weeks and 118.5% from 4 weeks ago. Deaths per day had been decelerating at a rapid rate in the United States but are now flattening out. The rate of decline has lessened as the increased infection rate and infectivity of the Omicron BA.1, BA.2 and particularly BA.2.12.1 variant of SARS CoV-2 have spread across the nation. The CDC estimates that BA.2.12.1 accounted for 36.5% of isolates in the week ending April 30.

Something to look out for is the rise of infections in South Africa from 25,393 infections in the 2 weeks ending on 4/22/22 to 71,869 infections in the last 14 days ending 5/6/22, a 283% increase. This is probably secondary to new Omicron mutants BA.4 and BA.5, which, according to NICD, became the dominant variants in South Africa in April, comprising 58% of isolates. According to the UK Health Security Agency, “BA.4 shares all mutations/deletions with the BA.2 lineage except the following: S: 69/70 deletion, R408 (WT, wild type)*, L452R, F486V, Q493 (WT); ORF 7b: L11F; N: P151S; synonymous SNP G12160A” and “BA.5 shares all mutations/deletions with the BA.2 lineage except the following: S: 69/70 deletion, R408 (WT), L452R, F486V, Q493 (WT); ORF6: D61 (WT); M: D3N; synonymous SNPs: G12160A, A27038G, and C27889T.” As of 5/8/22, the United States has sequenced 20 cases of BA.4 and 6 cases of BA.5. 

The Omicron variant will continue to mutate just like Delta. There are now 92 Omicron sub-variants that have been assigned Pango lineages, including 43 sub-lineages of BA.2.

An additional problem may be the development of recombinant SARS-CoV-2 isolates. A recombinant isolate occurs when two isolates infect the same cell and, in the process of viral reproduction, exchange nucleic acids, creating a new isolate that is a recombination of parts from the genomes of both isolates. A recombinant isolate of Delta AY.4.2.2 and Omicron BA.1.1 was recently reported in the UK. As of 3/25/22 four different recombinant variants of SARS-CoV-2 have been reported by the UK Health Security Agency. 

According to the UK Health Security Agency’s Technical Briefing from 3/25/22: “There are currently 3 recombinant lineages being monitored as part of horizon scanning: XD, XE, and XF (Figure 6). XD and XF are Delta and BA.1 recombinants. XE is a BA.1 and BA.2 recombinant and has 3 mutations that are not present in all BA.1 or BA.2 sequences: NSP3 C3241T and V1069I, and NSP12 C14599T. XF and XE are associated with UK sequenced samples. XD is predominantly associated with France. XD contains the unique mutation NSP2:E172D.”

As of 5/8/22 the UK Health Security Agency reports 1,880 sequences of the XE recombinant in the UK data. The figure below shows a breakdown of XE data by gender and age group. We can see there were more XE infections in children and young adults than there were in the 70+ age groups. 

Omicron variants have mutations which decrease the effectiveness of current vaccines and monoclonal antibodies. The effectiveness of the new Pfizer drug, PAXLOVIDTM, should not be compromised by any of the current mutations in Omicron or Delta variants. Pfizer completed their filing with the FDA on 11/15/21. The FDA approved PAXLOVIDTM on December 22 , 2021.The FDA approved Merck’s drug Molnupiravir on December 23, 2021. On 12/23/21 CVS announced by fax it was selected by the Government to distribute oral PAXLOVIDTM and Molnupiravir. On 12/27/21, another fax from CVS listed which CVS pharmacies in California would have these drugs. Monterey County covers 3,771 square miles with a population of 434,061. Three CVS pharmacies in Monterey, Salinas, and Soledad are the only listed pharmacies in our county. I have now been able to obtain PAXLOVIDTM for infected patients from the CVS in Salinas (phone 831-424-0026), the CVS on Fremont Street in Monterey (phone 831-375-5135) and the CVS in Soledad in south Monterey County (phone 831-678-5110). All require electronic prescriptions written as Paxlovid three tablets twice daily orally for five days (thirty total tablets).  Physicians or their staff probably should call to check on drug availability that day.

In the absence of obtaining intravenous Sotrovimab or Bebtelovimab, only oral PAXLOVIDTM and Molnupiravir are available to treat SARS-CoV-2 as an outpatient. Our first Paxlovid failure in an immunocompromised patient was treated the week of 4/5/22 at the Community Hospital of the Monterey Peninsula (Montage) ER as an outpatient with a single one-minute intravenous injection of Bebtelovimab. Vaccination will not prevent you from getting an Omicron variant infection. For now only masking (N95 rated masks, please!) and social distancing will have any effect on acquisition of infection with these variants. Furthermore, we do not believe that a 5-day quarantine or isolation period is sufficient for any COVID-19 infection.

On 5/06/22, the United States had 77,116 documented new infections. There were also 291 deaths. In the United States the number of hospitalized patients had been decreasing in many areas. Now there are 1,724  patients who are seriously or critically ill; that number was 1,512 two weeks ago. The number of critically ill patients has increased by 212 in the last 14 days, while at least 6,232 new deaths occurred (a decrease of 19 deaths per day from the previous 14 days). The number of critically ill patients has increased for the first time in nineteen 14-day periods. Patients are still dying each day (average 445/day). Omicron BA.2  variants causing infections should continue to increase and critically ill patients may continue to increase. Deaths usually lag two to four weeks behind exponential increase in infections so we will have to see how lethal BA.2.12.1 infections are in a month. Infections with a BA.1, and BA.2 will not prevent infections with BA.2.12.1. There have already been reports out of Israel of patients infected with BA.1 being later reinfected with BA.2. 

As of 5/06/22, we have had 1,024,386 deaths and 83,534,060 SARS-CoV-2 infections in the United States. We have had 905,971 new infections in the last 14 days. We were adding an average of 452,985 infections every seven days. For the pandemic in the United States we are averaging one death for every 81.5 infections reported for each death or over 12,263 deaths for each one million infections. As of 5/06/22, thirty-seven states have had greater than 500,000 total infections, and 36 states have had greater than 5,000 total deaths. Seventeen states (Virginia, Missouri, North Carolina, Indiana, Tennessee, Massachusetts, Ohio, Michigan, Georgia, Illinois, New Jersey, Pennsylvania, Florida, Texas, New York, Arizona and California) have had greater than 20,000 deaths. Four states (Florida, Texas, New York, and California) have had greater than 68,000 deaths. California and Texas have each had greater than 85,000 deaths with California having 90,804 deaths (20th most deaths in the world). 

On 11/20/20 in the United States, 3.70% of the population had a documented SARS-CoV-2 infection. California was ranked 41st in infection percentage at 2.77%. On 11/20/21 in North Dakota, 9.18% of the population was infected (ranked #1), and in South Dakota, 8.03% of the population was infected (ranked #2). As of 5/06/22, in the United States, 24.96% of the population has had a documented SARS-CoV-2 infection. In the last 17 months, 22.27% of our country became infected with SARS-CoV-2. On 11/20/20, there were 260,331 (cumulative) deaths in the US from SARS-CoV-2. In the last 17 months, there were 764,255 new deaths from SARS-CoV-2. For fourteen of those months, vaccines have been available to all adults. During these fourteen months, 453,289 people have died of SARS-CoV-2 infections. Most of the hospitalizations and deaths could have been prevented by vaccination, proper masking, and social distancing. 

As of 5/06/22, California was ranked 37th in infection percentage at 23.50%. In California 19.66% of Californians were infected in the last 17 months. As of 5/06/22 forty-five states have had greater than 20% of their population infected. Rhode Island was at 35,48% (ranked #1), Alaska was at 33.67% (ranked #2), North Dakota was at 31.72% (ranked #3), Kentucky was at 29.81% (ranked #4), Tennessee was at 29.78% (ranked #5), Utah was at 29.17% (ranked #6), South Carolina was at 28.69% (ranked #7), West Virginia was at 28.06% (ranked #8), Florida jumped to 27.97% (ranked #9). Wisconsin jumped to 27.87% (ranked #10), Arizona was at 27.82% (ranked #11), Arkansas was at 27.73% (ranked #12) and Texas was at 23.59% (ranked #36) of their population infected.

The table below shows that if we rank the US states with the highest death rates per million population within the world rankings, we see that Mississippi, Arizona and Alabama have the eighth highest death rates, New Jersey, Arkansas, West Virginia and Tennessee have the ninth highest COVID-19 deaths per million in the world. Louisiana had the tenth, New York was at eleventh,  Florida and Rhode Island were tied at twelth. The United States as a whole ranks 16th in the world for deaths per million population (3,095 deaths per million). California ranks 40th in the USA (and 36th in the world). If we look at the death rates per million in South Korea (452), Iceland (345), Japan (286), and Israel (1,152), they suggest that treatment outcomes are somehow different in these four countries. The same phenomenon can be seen in Scandinavia, where the death rate in Sweden is 1,839 per million, compared to 47 per million in Norway and 747 per million in Finland. The United States should have taken a closer look at how countries with low death rates (like South Korea, Iceland, Japan, Finland, and Norway) were preventing COVID-19 infections and treating COVID-19 patients. 

State or Country COVID-19 Deaths per million populationRank in USARanked within World
Mississippi4,1851st8th tied
New Jersey  3,7707th9th tied
Louisiana3,7168th10th 
New York 3,54413th11th 
Alabama3,9983rd8th tied
Arizona4,1482nd8th tied
Rhode Island  3,559  20th12th
Arkansas3,7806th9th tied
Florida3,44919th12th 
California2,29840th36th
USA3,09516th
Peru6,2961st
Bosnia-Herzegovina  4,8623rd
Hungary4,8124th
Montenegro4,3256th
Bulgaria5,3952nd
Czechia3,7429th
Brazil3,08416th
Georgia4,2297th
Sweden1,83957th
Israel1,15284th
Canada1,03691st
Finland747111th
Norway547125th
Japan286149th
Iceland345142nd
South Korea452129th

FDA-Approved Oral Drug Treatments for SARS-CoV-2

Pfizer has developed PAXLOVID™, an oral reversible inhibitor of C3-like protease of SARS-CoV-2. The drug inhibits this key enzyme that is crucial for virus production. The compound, also called Compound 6 (PF-07321332), is part of the drug combination PAXLOVID™ (PF-07321332; ritonavir), which just successfully completed a Phase 2-3 trial in humans in multiple countries. The preliminary results were announced on 11/5/21 by Pfizer. The results show that 89% of the hospitalizations and deaths were prevented in the drug treatment arm. The drug was administered twice a day for five days. No deaths occurred in the treatment group, and ten deaths occurred in the placebo group. The study was stopped by an independent data safety monitoring board, and the FDA concurred with this decision. Pfizer applied for an Emergency Use Authorization for this drug on 11/15/21. This drug was approved on 12/23/21. We have only been able to obtain PAXLOVID™ for two patients who we successfully treated with this drug obtained from CVS in Salinas (East Alisal Street; phone number 831-424-0026). They were expecting another shipment on 1/28/22. In my opinion, this agent, if more widely available, could markedly alter the course of every coronavirus infection throughout the world. 

Merck has developed the oral drug Molnupiravir, which induces RNA mutagenesis by viral RNA-dependent RNA polymerase of SARS-CoV-2 and other viruses. According to Kabinger et al, “Viral RNA-dependent RNA polymerase uses the active form of Molnupiravir, β-D-N4-hydroxycytidine triphosphate, as a substrate instead of cytidine triphosphate or uridine triphosphate. When the RNA-dependent RNA polymerase uses the resulting RNA as a template, β-D-N4-hydroxycytidine triphosphate directs incorporation of either guanine or adenine, leading to mutated (viral) RNA products. Analysis of RNA-dependent RNA polymerase–RNA complexes that contain mutagenesis products has demonstrated that β-D-N4-hydroxycytidine (the active form of Molnupiravir) can form stable base pairs with either guanine or adenine in RNA-dependent RNA polymerase explaining how the polymerase escapes proofreading and synthesizes mutated RNA” (quotation modified for clarity). The results of the phase 3 trial of Molnupiravir were published in the NEJM article “Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients” by Angélica Jayk Bernal, M.D. et al. (December 16, 2021 DOI: 10.1056/NEJMoa2116044). In this phase 3 study in the Molnupiravir group, 28 patients were hospitalized and one death occurred. In the placebo group, 53 patients were hospitalized and 9 died. Overall, 47% of hospitalizations and deaths were prevented by Molnupiravir. If you do a post hoc analysis and just look at deaths, Molnupiravir would prevent 89% of deaths. An Emergency Use Authorization by the FDA for Molnupiravir was approved on 12/24/21.The dose of Molnupiravir approved is four 200 mg capsules orally twice a day for five days. Diarrhea is reportedly a side effect in two percent of patients. I treated my first patient with Molnupiravir on 1/28/22. Currently more Molnupiravir is available weekly in the United States than PAXLOVID™ (see chart below; data from PHE.gov). Locally Molnupiravir is still available at CVS in Monterey (Fremont Blvd.; phone number: 831-375-5135) and CVS in Salinas (East Alisal Street; phone number 831-424-0026). 

FDA Approved Intramuscular Prophylaxis of SARS-CoV-2 Immunocompromised Patients

Evusheld (from AstraZeneca) contains two human monoclonal antibodies, Tixagevimab (150 mg in 1.5 mL) and Cilgavimab (150 mg in 1.5 mL), in separate vials. According to the manufacturer, “Tixagevimab and Cilgavimab are two recombinant human IgG1κ monoclonal antibodies with amino acid substitutions to extend antibody half-life (YTE), reduce antibody effector function, and minimize the potential risk of antibody-dependent enhancement of disease (TM). Tixagevimab and Cilgavimab can simultaneously bind to non-overlapping regions of the receptor binding domain (RBD) of SARS-CoV-2 spike protein. Tixagevimab, Cilgavimab, and their combination bind to spike protein with equilibrium dissociation constants of KD = 2.76 pM, 13.0 pM and 13.7 pM, respectively, blocking its interaction with human ACE2, the SARS-CoV-2 receptor, which is required for virus attachment. Tixagevimab, Cilgavimab, and their combination blocked RBD binding to human ACE2 with IC50 values of 0.32 nM (48 ng/mL), 0.53 nM (80 ng/mL), and 0.43 nM (65 ng/mL), respectively.” Each monoclonal antibody is administered intramuscularly to immunocompromised patients in two separate injections every six months. Evusheld availability in California is limited and has been rationed/distributed by our local Public Health Department only to hospitals. Physicians in Monterey County who want to receive a distribution (or redistribution) of Evusheld need to be added to the list of eligible facilities by the State Therapeutics group. The first step is for the Monterey County EMS Agency (phone: 831-755-5713) to make a request to the State Therapeutics group to have the facility added to the system for further verification.  Due to extremely limited availability, evidently the State Therapeutics group is currently only considering additions on a case by case basis.  Physicians who wish to submit their facility for consideration will need to provide the following information to the Monterey County EMS Agency:

  1. Facility/Provider Name for Registration
  2. Provider Type (Hospital, Pharmacy, Etc)
  3. Shipping Address
  4. Contact Name(s)
  5. Contact Email(s)
  6. Contact Phone Number(s)

As for my immunocompromised patients: We provided this information by email to the Monterey County EMS Agency on 1/26/22 and will update you when or if we become an eligible provider and receive our first doses of Evusheld. On 2/24/22, the FDA revised its dosing guidance for Evusheld, doubling the dosage of its two components, Tixagevimab and Cilgavimab, from 150 mg each to 300 mg each. They explain, “Based on the most recent information and data available, Evusheld may be less active against certain Omicron subvariants. The dosing regimen was revised because available data indicate that a higher dose of Evusheld may be more likely to prevent infection by the COVID-19 Omicron subvariants BA.1 and BA.1.1 than the originally authorized Evusheld dose.” Patients who have already received their first administration of Evusheld intramuscularly will need to contact their healthcare provider to get a second 150 mg injection of Tixagevimab and Cilgavimab. If you have not received Evusheld yet, the correct dose is 3 mL/300 mg of each monoclonal antibody injected intramuscularly. This large volume necessitates administration of the antibodies in the gluteus, with two separate injections.

A New Possible Indication for an Older FDA-Approved Antiviral Drug 

Remdesivir was the first FDA-approved Emergency Use Authorization drug for the treatment of SARS-CoV-2 infected patients. In their January 2021 paper in Nature Communications, Kokic et al explained the mechanism of Remdesivir’s action on SARS-CoV-2: “The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Addition of the fourth nucleotide following Remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RNA-dependent RNA polymerase. In the structure of the Remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease.” 

A recent study by Gottlieb et al of intravenous Remdesivir to prevent disease progression, whose design was similar to the study designs used for PAXLOVID™ and Molnupiravir, was published in the New England Journal of Medicine on 1/27/22. The study resulted in an 87% lower risk of hospitalization or death than in the placebo group with a similar adverse events occurrence (42.3% and 46.3% respectively). The FDA may allow approval of outpatient intravenous Remdesivir over three days (200 mg IV on day one followed by 100 mg IV daily on days two and three) in high risk non-hospitalized SARS-CoV-2 infected patients.

With the exception of Evusheld, all of the therapies listed above, with the exception of sotrovimab, can be used in Omicron-infected patients. Other previously approved monoclonal antibodies will not work for Omicron.

The Threat of SARS-CoV-2 Variants

In response to the need for “easy-to-pronounce and non-stigmatising labels,” at the end of May, the World Health Organization assigned a letter from the Greek alphabet to each SARS-CoV-2 variant. GISAID, Nextstrain, and Pango will continue to use the previously established nomenclature. For our purposes, we’ll be referring to each variant by both its Greek alphabet letter and the Pango nomenclature. 

The WHO has sorted variants into two categories: Variants of Concern (VOC) and Variants of Interest (VOI). The criteria for Variants of Concern are as follows:

  • Increase in transmissibility or detrimental change in COVID-19 epidemiology; or 
  • Increase in virulence or change in clinical disease presentation; or 
  • Decrease in effectiveness of public health and social measures or available diagnostics, vaccines, therapeutics.  

The WHO categorizes the following five variants as Variants of Concern (VOC):

Source: World Health Organization

The criteria for Variants of Interest (VOI) are as follows:

  • has been identified to cause community transmission/multiple COVID-19 cases/clusters, or has been detected in multiple countries; OR  
  • is otherwise assessed to be a VOI by WHO in consultation with the WHO SARS-CoV-2 Virus Evolution Working Group. 

The WHO categorizes the following six variants as Variants of Interest (VOI):

According to the UK Health Security Agency Technical Briefing from 2/25/22, “A putative Delta and Omicron recombinant has been identified in the UK, with likely parental lineages AY.4.2.2 and BA.1.1 and a breakpoint in non-structural protein 3 (nsp3). The presence of 34 genomes sampled between 7 January 2022 and 14 February 2022 suggest that this recombinant is able to transmit.” GISAID has also begun publishing data about a recombinant of Delta AY.4 and Omicron BA.1, first identified in France. According to GISAID data, this variant has also been detected in Denmark, Germany, the Netherlands, and the United States. Forbes 

We will need to monitor for this Delta-Omicron recombinant variant in the United States as well. 

Omicron cases sequenced as of 5/8/22:

GISAID

GISAID

Map of Omicron sequenced transmissions:

GISAID

Delta cases sequenced as of 5/8/22: 

GISAID

Map of Delta sequenced transmissions:

GISAID

GKA (AY.4/BA.1) cases sequenced as of 5/8/22:

GISAID

B.1.640 cases sequenced as of 5/8/22:

GISAID

Watching World Data

Over the next few months, we’ll be paying close attention to correlations between the SARS-CoV-2 data, the number of isolates identified in various countries and states, and the non-pharmaceutical interventions (like mask mandates and lockdowns) put in place by state and national governments. Data on infections, deaths, and percent of population infected was compiled from Worldometers. Data for this table for SARS-CoV-2 Isolates Currently Known in Location was compiled from GISAID and the CDC. It’s worth noting that GISAID provided more data than the CDC.

LocationTotal Infections as of 5/06/22New Infections on 5/06/22Total DeathsNew Deaths on 5/06/22% of Pop.InfectedSARS-CoV-2 Isolates Currently Known in LocationNational/ State Mask MandateCurrently in Lockdown
World516,495,714(7,985,986 new infections in 14 days).514,7036,274,548(34,384 new deaths in last 14 days)2,0066.62%B2 lineageAlpha/B.1.1.7 (UK)Eta/B.1.525 (Nigeria/UK)Iota/B.1.526 (USA-NYC)Beta/B.1.351 (SA)Epsilon/B.1.427 + B.1.429 (USA)*Gamma/P.1 (Brazil)Zeta/P.2 (Brazil)A lineage isolateV01.V2 (Tanzania)APTK India VOC 32421Delta/B.1.617.2 (India)BV-1 (Texas, USA)Kappa/B.1.617.1 (India)Lambda/C.37 (Peru)Theta/P.3 (Philippines) Mu/B.1.621 (Colombia)C.1.2 (South Africa 2% of isolates in July 2021)R1 (Japan)Omicron/B.1.1.529 + BA.1 + BA.2 + BA.3 (South Africa November 2021)B.1.640.1 (Congo/France)B.1.640.2 (Cameroon/France)Four new recombinants 12/31 to 3/22)NoNo
USA83,534,060(ranked #1) 905,971 new infections in the last 14 days.77,116(ranked #2)1,024,386(ranked #1)6,232 new deaths in the last 14 days. 29124.96%B2 lineageAlpha/B.1.1.7 (UK)Eta/B.1.525 (Nigeria/UK)Iota/B.1.526 (USA-NYC)Beta/B.1.351 (SA)Epsilon/B.1.427 + B.1.429 (USA)*Gamma/P.1 (Brazil)Zeta/P.2 (Brazil)Delta/B.1.617.2 (India)BV-1 (Texas, USA)Theta/P.3 (Philippines) Theta/P.3 (Philippines) Kappa/B.1.617.1 (India)Lambda/C.37 (Peru)Mu/B.1.621 (Colombia)R1(Japan)         Omicron/B.1.1.529 + BA.1 + BA.2 (South Africa November 2021)B.1.640.1 (Congo/France)Recombinant Delta AY.119.2- Omicron BA.1.1 (Tennessee, USA 12/31/21)NoNo
Brazil30,543,908(ranked #3) 497,143 new infections in the last 14 days. 19,725 (ranked #9)664,143(ranked #2)17814.18%B2 lineageAlpha/B.1.1.7 (UK)Beta/B.1.351 (SA)Gamma/P.1 (Brazil)Zeta/P.2 (Brazil)Lambda/C.37 (Peru)Mu/B.1.621 (Colombia) Omicron/B.1.1.529 + BA.1 (South Africa November 2021)NoNo
India43,018,032(ranked #2); 44,151 new infections in 2 weeks.4,195524,024(ranked #3)223.06%B2 lineageAlpha/B.1.1.7 (UK)Beta/B.1.351 (SA)Gamma/P.1 (Brazil)Epsilon/B.1.427 + B.1.429 (USA)*Eta/B.1.525 (Nigeria/UK)APTK India VOI 32421Delta/B.1.617.2 (India)Kappa/B.1.617.1 (India)Iota/B.1.526 (USA-NYC) Omicron/B.1.1.529 + BA.1 (South Africa November 2021)B.1.640.1 (Congo/France)NoNo
United Kingdom22,114,034(ranked #6; was #6 thirty-two weeks ago; 180,828 new infections in 2 weeks.6,551(ranked 15th in the world).176,212(ranked #7 in world)22832.26%B2 lineageAlpha/B.1.1.7 (UK)Eta/B.1.525 (Nigeria/UK)Beta/B.1.351 (SA)Epsilon/B.1.427 + B.1.429 (USA)*Gamma/P.1 (Brazil)Delta/B.1.617.2 (India)Theta/P.3 (Philippines) Kappa/B.1.617.1 (India)Lambda/C.37 (Peru)Mu/B.1.621 (Colombia)C.1.2 (South Africa)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)B.1.640.1 (Congo/France)XD (AY.4/BA.1) recombinantXF (Delta/BA.1) recombinantXE (BA.1/BA.2) recombinantNoNo
California, USA9,288,773(ranked #13 in the world;  44,240 new infections in the last 14 days).39,51490.804 (ranked #20 in world)5523.50%B2 lineageAlpha/B.1.1.7 (UK)Eta/B.1.525 (Nigeria/UK)Beta/B.1.351 (SA)Gamma/P.1 (Brazil)Epsilon/B.1.427 + B.1.429 (USA)*Zeta/P.2 (Brazil)Delta/B.1.617.2 (India)Theta/P.3 (Philippines) Kappa/B.1.617.1 (India)Lambda/C.37 (Peru) Mu/B.1.621 (Colombia) Omicron/B.1.1.529 + BA.1 (South Africa November 2021)NoNo
Mexico5,740,080(ranked #20) 8,445 new infections in 14 days).———324,350(ranked #5)——–4.36%B2 lineageAlpha/B.1.1.7 (UK)Epsilon/B.1.427 + B.1.429 (USA)*Gamma/P.1 (Brazil)Delta/B.1.617.2 (India)Kappa/B.1.617.1 (India)Lambda/C.37 (Peru)Mu/B.1.621 (Colombia)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)NoNo
South Africa3,827,378(ranked #30; 71,869 new infections in 14 days).9,253100,505 (ranked #18)346.30%B2 lineageAlpha/B.1.1.7 (UK)Beta/B.1.351 (SA)Delta/B.1.617.2 (India)Kappa/B.1.617.1 (India)       C.1.2 (South Africa, July 2021)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)B.1.640.1 (Congo/France)NoNo
Canada3,787,378(ranked #27, was 26th sixteen weeks ago; 95,613 new infections in 14 days).8,55737,977(ranked #26)429.29% .B2 lineageAlpha/B.1.1.7 (UK)Eta/B.1.525 (Nigeria/UK)Epsilon/B.1.427 + B.1.429 (USA)*Gamma/P.1 (Brazil)Delta/B.1.617.2 (India)Kappa/B.1.617.1 (India)Lambda/C.37 (Peru)Mu/B.1.621 (Colombia)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)B.1.640.1 (Congo/France)NoNo
Poland5,999,513(ranked #19; 43,262 new infections in 14 days). 607116,124 (ranked #15)2615.88%B2 lineageAlpha/B.1.1.7 (UK)Eta/B.1.525 (Nigeria/UK)Beta/B.1.351 (SA)Delta/B.1.617.2 (India)Mu/B.1.621 (Colombia)Omicron/B.1.1.529 + BA.1 + (South Africa November 2021),Omicron/B.1.1.529 +BA.3 NoNo
Turkey15,040,238(ranked #10, 26,622 new infections in 14 days).1,74398,826 (ranked #19)717.48% B2 lineageAlpha/B.1.1.7 (UK)Eta/B.1.525 (Nigeria/UK)Beta/B.1.351 (SA)Epsilon/B.1.427 + B.1.429 (USA)*Gamma/P.1 (Brazil)Lambda/C.37 (Peru)Mu/B.1.621 (Colombia)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)B.1.640.1 (Congo/France)NoNo
Russia18,216,719(ranked #7), 96,857 new infections in 14 days).5,541376,696(ranked #4 in world)13612.47%B2 lineageAlpha/B.1.1.7 (UK)Beta/B.1.351 (SA)Delta/B.1.617.2 (India)R1 (Japan) B.1.640.1 (Congo/France)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)NoNo
Argentina9,083,673(ranked #13; 22,650 new infections in 14 days).———–128,194 (ranked #14 in world)——–19.76%B2 lineageAlpha/B.1.1.7 (UK)Eta/B.1.525 (Nigeria/UK)Beta/B.1.351 (SA)Epsilon/B.1.427 + B.1.429 (USA)*Gama/P.1 (Brazil)Delta/B.1.617.2 (India)Lambda/C.37 (Peru)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)NoNo
Colombia6,093,645(ranked #18, 2,842 new infections in 14 days).———–139,809 (ranked #12 in the world)———11.74%B2 lineageAlpha/B.1.1.7 (UK)Beta/B.1.351 (SA)Gamma/P.1 (Brazil)Delta/B.1.617.2 (India)Epsilon/B.1.427 + B.1.429 (USA)*Iota/B.1.526 (USA-NYC)Lambda/C.37 (Peru)Mu/B.1.621 (Colombia)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)NoNo
Peru3,569,026(ranked #35, 9,683 new infections in 14 days). 334212,913(ranked #6)710.55%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India)Gamma/P.1 (Brazil)Iota/B.1.526 (USA-NYC)Lambda/C.37 (Peru)Mu/B.1.621 (Colombia)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)NoNo
Indonesia6,097,986(ranked #18; 54,720 new infections in 14 days)245156,357 (ranked #9)172.16%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India)Beta/B.1.351 (SA)Eta/B.1.525 (Nigeria/UK)Theta/P.3 (Philippines) Iota/B.1.526 (USA-NYC)Kappa/B.1.617.1 (India)B.1.640.1 (Congo/France)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)
NoNo
Iran7,224,431 9,527 new infections in last 14 days(ranked 16th; was 12th  thirty-two weeks ago)375141,157 (ranked #11)128.40%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India)Beta/B.1.351 (SA)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)


NoNo
Spain12,009,059(ranked 11th;   381,572  new infections in 14 days).18,526104,869 (ranked #17)6725.66%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India)Beta/B.1.351 (SA)Gamma/P.1 (Brazil)Epsilon/B.1.427 + B.1.429 (USA)*Eta/B.1.525 (Nigeria/UK)Iota/B.1.526 (USA-NYC)Kappa/B.1.617.1 (India)Mu/B.1.621 (Colombia)Omicron/B.1.1.529 + BA.1 (South Africa November 2021)B.1.640.1 (Congo/France)NoNo
France28,890,139 (ranked #4; 725,733 new infections in the last 14 days).40,224 (ranked #4)146,608 (ranked #10)11044.08%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India) Omicron/B.1.1.529 South Africa November 2021)B.1.640.1 (Congo/France)B.1.640.2 (Cameroon/France)GKA (AY.4/BA.1) recombinantNoNo
Germany25,289,590(ranked #5; 1,279,822 new infections in 14 days.).86,026 (ranked #1)136,812 (ranked #13)33630.00%
B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India) Delta/B.1.617.2 (India) Omicron/B.1.1.529 South Africa November 2021)GKA (AY.4/BA.1) recombinantNoNo
Hungary1,903,200 (ranked #43; 12,237new infections in 14 days).
———46,266 (ranked #23)——–19.79%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India) Delta/B.1.617.2 (India) Omicron/B.1.1.529 South Africa November 2021)NoNo
Romania2,898,258(ranked #38; 11,000 new infections in 14 days).73065,554 (ranked#20)915.25%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India) Delta/B.1.617.2 (India) Omicron/B.1.1.529 South Africa November 2021)NoNo
South Korea17,464,782 (ranked 8th) ; 709,727 new infections in 14 days).26,714(ranked#7)23,206 (ranked #39); 4834.01%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India) Delta/B.1.617.2 (India) Omicron/B.1.1.529 South Africa November 2021)NoNo
Ukraine5,002,870(ranked #22; 20,621 new infections in 14 days),——–108,411 (ranked #16)——–11.56%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India) Delta/B.1.617.2 (India) Omicron/B.1.1.529 South Africa November 2021)NoNo
Vietnam10,670,570(ranked #12; 126,246 new infections in 14 days).3,81943,051 (ranked #24)610.78%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India) Delta/B.1.617.2 (India) Omicron/B.1.1.529 South Africa November 2021)NoNo
Netherlands8,057,700 (ranked #14; 22,097 new infections in 14 days).1,30322,270 (ranked #41)146.83%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India) Delta/B.1.617.2 (India) Omicron/B.1.1.529 South Africa November 2021)GKA (AY.4/BA.1) recombinantNoNo
Denmark2,970,809, (ranked #37) 12,283  new infections in 14 days8076,266 (ranked #81)850.95%B2 lineageAlpha/B.1.1.7 (UK)Delta/B.1.617.2 (India) Delta/B.1.617.2 (India) Omicron/B.1.1.529 South Africa November 2021)GKA (AY.4/BA.1) recombinantNoNo




What Our Team Is Reading This Week

COVID-19

SARS-CoV-2 Update

It’s time for our next 14-day moving average determinations and projections for infections and deaths from SARS-CoV-2 for the United States and my thoughts on vaccines and mutant viruses. We use the WORLDOMETERS aggregators data set to make our projections of future total infections and deaths since it includes data from the Department of Veterans Affairs, the U.S. Military, federal prisons and the Navajo Nation.

In the United States, SARS-CoV-2 deaths have decreased for the second time in a 14-day period. There were 492 fewer deaths per day than in the last 14-day period. In the last 14 days, the number of infections has decreased by 14,033 infections per day. This decrease in infections over the last four 14-day periods may represent increased mask usage and social distancing, which are a part of the Biden 100-day SARS-CoV-2 plan (day 52 of plan). On 3/12/21, 66,785 new infections occurred in the United States. There were also 1,505 deaths. The number of hospitalized patients is decreasing, and only 11,670 patients are critically ill. The number of critically ill patients has decreased by 3,808 in the last 14 days, while 21,534 new deaths occurred. This suggests that the number of critically ill patients is decreasing because a large number of patients are dying. 

As of 3/12/21, we have had 545,545 deaths and 29,993,423 SARS-CoV-2 infections in the United States. We have had 820,681 new infections in the last 14 days. We are adding 410,340 infections every 7 days. Each million infections usually results in at least 20,000 deaths. On 3/12/21, twenty states have had greater than 500,000 total infections, and 30 states had greater than 5,000 total deaths. 

On 11/20/20 in the United States, 3.70% of the population had a documented SARS-CoV-2 infection. California was ranked 41st in infection percentage at 2.77%. In North Dakota 9.18% of the population was infected (ranked #1), and in South Dakota 8.03% of the population was infected (ranked #2).

As of 3/12/21, in the United States 9.02% of the population has had a documented SARS-CoV-2 infection. In the last 3.5 months 5% of our country became infected with SARS-CoV-2. 

As of 3/12/21, California was ranked 29th in infection percentage at 9.02%. In North Dakota 13.23% of the population was infected (ranked #1) and in South Dakota 12.92% of the population was infected (ranked #2). Thirty states have greater than 9% of their population infected and 44 states have greater than 6% infected. Only four states have less than 4% of their population infected: Oregon (3.77%), Maine (3.47%), Vermont (2.66%), and Hawaii (1.98%). 

New Mutants

A new mutant SARS-CoV-2 virus (lineage B.1.1.7), first seen in the UK in September, has now been found in multiple other countries. There are 3,170 reported cases in the US as of 3/11/21. This isolate has now been found in 49 states and the District of Columbia. This isolate (let’s call it Lineage B.1.1.7 or SARS-CoV-2 UK) is more infectious than other previously circulating B2 lineage isolates. There are two deletions and six other mutations in its spike protein. One mutation involves a change of one amino acid, an asparagine at position 501 in the receptor binding motif with a tyrosine. This enhances binding (affinity) to the ACE-2 receptor and may alone be responsible for the increased infectivity of this isolate. A study published March 10 in the British Medical Journal (BMJ) found that the risk of death increased by 64% in patients infected with the B.1.1.7 variant compared to all other isolates. Due to air and other travel, this isolate will become the dominant isolate worldwide. 

B.1.351, also known as the South African isolate, has 108 reported cases and has occurred in 23 states and the District of Columbia. The P.1 isolate (Brazil) has 17 reported cases and has been found in 10 states. (This data is available at https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant-cases.html)

A disturbing report out of the UK has found a second mutation in B.1.1.7. This mutation, which occurs in the loop sequence has also been found in the South African (B.1.351) and Brazilian (P.1) variants. (The loop sequence is in the receptor binding motif in the receptor binding domain of the S1 sequence of the spike protein.) This mutation involves a change of one amino acid of the spike protein, number 484, from glutamic acid to lysine. This point mutation allows the virus to bind better to the ACE2 receptor, which increases infectivity. People who are exposed to one of these variants (versus the old B2 isolate) are more likely to be infected and are more likely to transmit the virus to others. 

In our last three updates we summarized a research letter published in Clinical Infectious Diseases about a patient in the UK who was first infected in April with a B2 isolate and experienced only mild symptoms but was infected with the new B.1.1.7 variant in December and became critically ill. The patient described in this research letter was not protected by a natural infection with a B2 lineage SARS-CoV-2 isolate in April 2020 from having a potentially lethal second infection with a B.1.1.7 lineage variant in December 2020, suggesting that folks who have had a past SARS-CoV-2 infection should not expect to have any immunity to new variants such as B.1.1.7. All of the currently available vaccines were developed with spike protein from B2 lineages. Moderna, Pfizer, and AstraZeneca/Oxford are currently remaking their spike protein vaccines to address the mutations in the South African variant of SARS-CoV-2 because the AstraZeneca/Oxford vaccine did not work in a small trial in South Africa, where most of the patients had the South African mutant (B.1.351). 

A California Mutant

A fourth mutant isolate of SARS-CoV-2, B.1.429 + B.1.427 (CAL.20C), has been identified in California. This isolate does not have any of the mutations mentioned above, but contains five mutations, three of which are in the spike protein, but not in the receptor binding motif. This mutant may be partially responsible for the massive increase in infections in California, to include infections of people who had already recovered from a SARS-CoV-2 infection earlier. In California to date, we have had 3,618,594 infections and 55,455 total deaths. California is averaging 249 deaths per day in the last 14 days. Currently, 9.15% of the population in California is infected. Nationally, we rank 29th in the percentage of people in the state infected. To my knowledge, only one privately held company is currently modifying their vaccine to cover the B.1.429 + B.1.427 mutant. 

Watching the Data

Over the next few months, we’ll be paying close attention to correlations between the SARS-CoV-2 data, the number of isolates identified in various countries and states, and the non-pharmaceutical interventions (like mask mandates and lockdowns) put in place by state and national governments. Data on infections, deaths, and percent of population infected was compiled from Worldometers. Data for this table for SARS-CoV-2 Isolates Currently Known in Location was compiled from GISAID and the CDC. It’s worth noting that GISAID provided more data than the CDC. 

SARS-CoV-2, Children, and MIS-C/PIMS

I’m pleased to see that COVID-19 cases and MIS-C (PIMS) cases in children in the US are finally getting national attention. The CDC now tracks total MIS-C cases and deaths in children and young adults up to 20 years old in the United States. As of March 1, CDC reported 2,617 cases of MIS-C that meet the case definition and 33 deaths. 

Source: https://www.cdc.gov/mis-c/cases/index.html

Schools in the United States have been open throughout the pandemic, with teachers and education support professionals demonstrating their extraordinary ability to adapt in adverse circumstances. Teachers all over the country reinvented their teaching, taking their classrooms online in order to provide safe and remote learning experiences for students. The so-called “reopening” of schools, which more accurately refers to the opening of school buildings, as schools never closed, has been highly politicized, with many governors issuing mandates for in-person instruction, even as case counts, hospitalizations, and deaths in their states rose exponentially. The CDC has maintained that transmission risk in schools is minimal, provided that adequate safety measures are taken; however, we know that many states have not properly enforced universal masking (and some are repealing mask mandates this week), and we know that many school facilities are not equipped with the proper air handling systems. With more school buildings opening, there is a growing body of research that suggests that COVID-19 transmission can and does happen in schools. 

After recommending for months that school buildings be open, in mid-February (a year into the pandemic), The American Academy of Pediatrics, in collaboration with the Children’s Hospital Association, finally began tracking data on COVID-19 in children at the state and national level. Data reporting by states is still voluntary, and every state is different in its willingness to collect and disclose data on infections, hospitalizations, deaths, and testing rates in children. 

As of the APA’s March 4 report, only 11 states provide age distribution for testing. This makes it difficult to hold states accountable for testing each age group in proportion to its population. We’ve seen a trend in states where testing data with age distribution is available that children are tested at lower rates than adults. Hospitalization data by age group is only available in 24 states and New York City, so we only understand the severity of COVID-19 infections in children for about half the country. Age distribution for cases is provided by 49 states, New York City, the District of Columbia, Puerto Rico, and Guam. It’s worth noting that New York State does not provide age data for cases, testing, hospitalizations, and deaths. Two states, Florida and Utah, only report cases in children aged 0-14, so the number of cases, hospitalizations, and deaths in children ages 15-17 is unknown in these states. 

As of March 4, A total of 256 child deaths due to COVID-19 were reported in 43 states. In the United States, The following states do not report child mortality due to COVID-19: Michigan, Montana, New Mexico, New York, Rhode Island, South Carolina, and West Virginia. Texas only reports age data for 3% of confirmed COVID-19 cases, so state-level data from Texas is extremely limited for assessing the incidence of COVID-19 in children. Even considering this, Texas reported 44 child deaths. Arizona reported 24, California 14, Georgia 10, Illinois 16, Maryland 10, and New York City 21. 

The United Kingdom tracks hospitalizations by age group, and with the increased incidence of B.1.1.7 saw the number of child hospitalizations double from November 2020 to January 2021. This data likely influenced the decision to close school buildings and go into total lockdown there on January 4, 2021. If we truly want to keep children safe, especially as many school buildings open for in-person instruction, we need to collect more complete data in every state on child testing rates, cases, hospitalizations, and deaths.

The Road Ahead

We are just on Day 66 of the Biden-Harris administration.The President has made the pandemic a first priority and has now ordered enough vaccine to vaccinate everyone who wants a vaccination by July 2021. We are currently vaccinating two million people a day in the United States and may vaccinate another 80 million people over the next 34 days. Testing, wearing masks, social distancing and washing our hands frequently should no longer be political issues. These are non-pharmaceutical interventions used by most successful countries and some states to protect their citizens and their economies. New Zealand, Taiwan, and Australia are three countries that have done this successfully.  In the United States, Vermont and Hawaii are doing a better job handling the pandemic than many of our states. These interventions with vaccination should keep the pandemic from overwhelming our health care delivery system. New mutations like B.1.429 + B.1.427 (Cal.20C), the UK, Brazillian and South African variants will probably spread rapidly throughout the United States over the next 90 days as several states (including Texas, Florida, Iowa, Mississippi) open up everything and do away with masking and social distancing. We should start seeing increased numbers of infections occurring in the United States over the next 30 days. At least one mutant from the UK, B.1.1.7, has increased the number of infections, hospitalizations and deaths. This mutant may do the same thing in the USA.

The Pfizer and Moderna RNA vaccines and the Johnson & Johnson single dose vaccination adenovirus vaccine are all being used to immunize people in the USA. The Oxford-AstraZeneca vaccine and Novavax vaccine should also be available in the second quarter of 2021. The current goal of the Biden administration in the US is to vaccinate everyone who wants a vaccine by July 1, 2021. If vaccine is available, another 180 million people could  be vaccinated. That’s good news. We are averaging 2 million vaccinations a day after having opened mass vaccination sites in multiple cities and states. 

The bad news is that all currently available vaccines are based on the Chinese spike protein sequence from December 2019. Mutated isolates, as discussed above, may overtake our ability to produce new vaccines and vaccinate the populace. Like Influenza vaccines, we may have to reformulate vaccines based on active, worldwide surveillance at least every 4 to 6 months. The FDA is currently putting together a guidance document for how to develop booster vaccines for SARS-CoV-2 mutations. A surrogate marker of protection like antibody to the mutated Receptor Binding Domains of SARS-CoV-2 should be considered for vaccine approval. 

I feel the current approach of companies and governments of making new vaccines against just the South African variant is wrong. The ideal approach to these spreading major mutations on at least four continents would be to make vaccines against each of the mutations. I’d get all of the vaccine companies and contract production companies on a call and “suggest” that two companies at least make and mass produce each of the four mutations. The government would pay the cost and buy at least 200 million doses in advance for each variant at say $40 a dose. The total cost to purchase the vaccine (800 million doses) would only be 32 billion dollars. Give each company a billion dollars each for development costs (another 8 billion dollars). Spend another two billion dollars for syringes and you’ve got enough booster doses to vaccinate 200 million people for all 4 variants. 42 billion dollars would be a small price to pay to catch up with the current mutations. Even if you had to do this every two years, it would be well worth the dollars spent. 

We still need to perform more virus isolations and perform more DNA sequencing of viruses in each country, state, populous city, and county if we are to rapidly identify new mutations. I’m more hopeful that we will have the facilities, the equipment, and the trained staff needed to perform this work. As a nation we are finally preparing to make more vaccine, new vaccines directed against mutants, and the necessary rapid tests and protective equipment needed by medical staff, first responders, essential workers and especially teachers and students. I’m still hopeful we can work together on our and the world’s infectious disease problems. 

COVID-19

Check out Dr. Wright’s new vlog: Close Reading COVID-19!

Close Reading COVID-19 is hosted by Dr. Wright and his daughter Emily, who has served as Dr. Wright’s research assistant since 2011. In this program, we take a deep dive into the research on SARS-CoV-2 using the same close reading strategies that Emily, a high school English teacher, uses with her students.

In the very first episode of Close Reading COVID-19, we take a look at the research on SARS-CoV-2 Variant of Concern B.1.1.7, which was first detected in the United Kingdom in fall of 2020 and has now been detected in 45 states in the US. We also examine hospitalization data to see how B.1.1.7 might be affecting youth in the UK and explore the data on PIMS/MIS-C, the inflammatory syndrome that some children and young adults develop after a COVID-19 infection. Finally, Dr. Wright offers his advice on masking, indoor gatherings, and vaccinations.

For links to the articles mentioned in the program, check out the slide show.