With several more emergency use authorizations (EUAs) across the globe, COVID-19 efforts to flatten the emerging variants with cocktail therapies and tweaked vaccines are frantically underway.

BioWorld has tracked 884 therapeutics and vaccines that have entered development for the deadly SARS-CoV-2 virus since it first emerged more than a year ago, and the U.S. government has now provided EUAs to three vaccines and six therapies.

As of March 1, the World Health Organization (WHO) reports more than 113.8 million cases and 2.53 million deaths from the pandemic, with U.S. figures standing at 28.2 million and 508,584, respectively. After three months of the first phase of global vaccinations, the number of cases and deaths appear to be heading downward, according to data collected by Johns Hopkins University.

Nevertheless, WHO has highlighted disparities in providing the vaccines. More than 75% of the 128 million doses administered globally has gone to 10 developed countries that cover 60% of the global gross domestic product. WHO also has rejected accidental laboratory escape in Wuhan, China, as the source of the SARS-CoV-2 virus, suggesting that the most likely route was not through horseshoe bats, but through an intermediary animal species, such as live or frozen animal, seafood or meat products.

Third vaccine gains EUA in U.S.

Granted an EUA by the FDA over the weekend, Johnson & Johnson’s adenoviral vector candidate, JNJ-78436735, became the third COVID-19 vaccine authorized in the U.S., behind Comirnaty (Pfizer Inc./Biontech SE) and mRNA-1273 (Moderna Inc.). It is the first single-shot vaccine.

Outside of the U.S., several others have gained conditional approvals, including the Gamaleya Research Institute of Epidemiology and Microbiology’s Sputnik V, armed with a 91% efficacy readout, and three vaccines developed in China.

Regulatory agencies in the U.S. and Europe are urging vaccine developers to test against emerging variants. Comirnaty and mRNA-1273 appear to be effective against the U.K (B.1.1.7), South Africa (B1.351) and Brazil (P.1) variants, and J&J’s candidate shows 66% efficacy against B1.351 with some efficacy against P.1 as well. In a follow-up study of Astrazeneca plc’s AZD-1222, the viral vector vaccine remains effective against the B.1.1.7 variant, despite lower neutralizing antibodies, but it has shown minimal protection against mild to moderate COVID-19 infection caused by the B1.351 variant.

While U.K. studies suggest antibodies after natural infection and vaccination provide protection for at least three months, companies are exploring the likely need for boosters.

Vaccine highlights in February include:

  • Briefing documents suggested the U.S. EUA would be granted for J&J’s recombinant adenoviral vector single-dose vaccine, JNJ-78436735 (Ad26.COV2.S), and it was on Feb. 27 for those 18 and older. The company also submitted a conditional MAA to the EMA, an emergency use listing request to WHO, and it began a rolling review in South Africa.
  • Phase III data of Russia’s Sputnik V (Gam-COVID-Vac) confirmed 91%-plus efficacy, as published in The Lancet on Feb. 2. In addition to Russia, the vaccine has gained EUAs in more than two dozen countries throughout Central and South America and Asia. Russia also has approved two other vaccines prior to phase III data: the inactivated whole virus vaccine Kovivac and the peptide vaccine Epivaccorona.
  • Comirnaty can be maintained in pharmaceutical freezers and refrigerators at much warmer temperatures than initially thought. Also, data published in The Lancet show the vaccine was 85% effective 15 to 28 days after the first dose for Israeli health care workers.
  • Moderna shipped trial doses of mRNA-1273.351, which addresses the South Africa variant, to the U.S. National Institute of Allergy and Infectious Diseases for testing. The company is working on a multivalent booster candidate, mRNA-1273.211, and testing a third dose of mRNA-1273 as a booster at the 50-ug dose level.

In terms of supply, the U.S. government exercised an option for an additional 100 million doses of Comirnaty for $1.95 billion, and another 100 million doses of mRNA-1273, bringing the total orders to 300 million of each vaccine. The European Commission also bought another 200 million doses of Comirnaty and another 150 million of mRNA-1273.

In the U.K., vaccinations, are dramatically reducing hospital admissions by 85% for those who received Comirnaty and by 94% for those who received AZD-1222, four weeks following the first dose. In people over 80, the overall reduction was 81%. The U.K. is now studying in 820 volunteers a combination of Comirnaty and AZD-1222.

  • AZD-1222 is provisionally approved in Australia, as is Comirnaty, and WHO granted it emergency use listing as COVID-19 Vaccine Astrazeneca and as Covishield. It also gained an EUA in Colombia after it showed 76% efficacy after one dose.
  • Novavax Inc. started its rolling review process for its protein subunit vaccine, NVX-CoV2373, in the U.S., Europe, the U.K. and Canada, as it completes pivotal phase III trials. It has shown efficacy against both the U.K. and South Africa variants.
  • Sinovac Biotech Ltd.’s inactivated virus vaccine, Coronavac, received conditional approval in China with an efficacy rate 14 days after dosing of 50.65% for all cases, 83.7% for cases requiring medical treatment, and 100% for hospitalized, severe and fatal cases. China also granted conditional approval for Cansino Biologics Inc.’s adenovirus vector vaccine, Convidecia (Ad5-nCoV), and for Sinopharm subsidiary Wuhan Institute of Biological Products’ inactivated vero cell vaccine.
  • Curevac AG’s mRNA candidate, CVnCoV, entered a phase IIb/III trial in Europe and Latin America with more than 35,000 participants. The company also partnered with Glaxosmithkline plc in a $180 million deal to develop a second-generation mRNA vaccine to address multiple variants. Curevac initiated a rolling submission with the EMA.

Disappointing or mixed vaccine news during February involved Vaxart Inc. and Sanofi SA.

  • Vaxart’s shares (NASDAQ:VXRT) plummeted 57.8% on Feb. 3 when phase I data showed neutralizing antibodies were not detected in most of the five subjects given two doses of VXA-CoV2-1, a non-replicating Ad5 vector vaccine, although the candidate triggered a strong CD8+ cytotoxic T-cell response and was generally well-tolerated.
  • Sanofi and Glaxosmithkline are refining the concentration of antigen in their protein subunit vaccine candidate after phase I/II results showed an insufficient response in older adults.

Of the 884 candidates that have entered development for COVID-19, 208 are vaccines and 676 are therapeutics.

Antibody cocktails addressing variants

At the forefront of therapeutic options, the FDA granted an EUA for bamlanivimab (LY-CoV555, Eli Lilly and Co./Abcellera Biologics Inc.) 700 mg and etesevimab (LY-CoV016, Junshi Biosciences Co. Ltd./Eli Lilly) 1,400 mg as a cocktail for treating mild to moderate COVID-19 in patients 12 and older at high risk for progressing to severe disease and/or hospitalization.

More companies are experimenting with cocktails to battle the variants. One involving Celltrion Group’s monoclonal antibody CT-P59 (regdanvimab) with another MAb candidate has demonstrated neutralizing capability against the U.K. and South Africa variants. CT-P59 gained an EUA in Korea in February.

Positive data led to Immunome Inc.’s stock (NASDAQ:IMNM) rising 75.6%, after IMM-BCP-001 was able to neutralize several SARS-CoV-2 variants. The company intends to begin clinical testing in the first half of 2021.

The first cocktail to receive an EUA in the U.S., Regeneron Pharmaceuticals Inc.’s Regen-Cov (casirivimab/imdevimab), showed clear clinical phase III efficacy in reducing the rate of hospitalization and death with both the 1,200-mg and 2,400-mg doses, prompting an independent data monitoring committee to recommend stopping enrollment. The EMA’s Committee for Medicinal Products for Human Use later issued a positive opinion for the cocktail.

In addition to addressing variants, researchers also are concentrating on COVID-19 long-haulers, or those who continue to experience symptoms long after recovering from the SARS-CoV-2 virus. And they are working toward diversity in clinical trials, with trade groups pushing for more research on those excluded, including pregnant and lactating women and the long-term care population. The U.S. NIH is funding a trial of Gilead Sciences Inc.’s Veklury (remdesivir) in treating COVID-19 in pregnant women, and a phase II/III study began in February testing Comirnaty in healthy pregnant women over 18.

In other therapeutics news:

  • In an exploratory study, Tiziana Life Sciences plc’s foralumab, an anti-CD3 monoclonal antibody, led to 80% lung CT scan improvement when used alone, and 75% improvement when combined with dexamethasone, vs. 43% for control.
  • Chugai Pharmaceutical Co. Ltd.’ interleukin-6 inhibitor, Actemra (tocilizumab) showed in the J-Covacta phase III trial that 72.9% of hospitalized patients with severe COVID-19 pneumonia were discharged or ready for discharge 28 days after treatment, while 10.4% died.
  • A primary phase II endpoint of Immunic Inc.’s IMU-838 (vidofludimus calcium), an oral dihydroorotate dehydrogenase inhibitor, could not be evaluated because less than 1% of those enrolled required ventilation during the study. The study also failed to demonstrate any difference with placebo on the 28-day survival and the need for ICU care, but it did lead to a higher likelihood of clinical recovery.
  • Celltrion Inc.’s monoclonal antibody, Regkirona (regdanvimab, CT-P59), gained conditional marketing authorization in South Korea for those over 60 and at higher risk, as well as for adults with mild or moderate symptoms. Phase III trials are underway in other countries.
  • Interleukin-6 inhibitor Roactemra (tocilizumab) reduces mortality in hospitalized COVID-19 patients, according to the 4,000-patient U.K. Recovery trial. In total, 596 (29%) of treated patients died within 28 days v. 694 (33%) of standard-of-care (dexamethasone) group patients (p=0.007).
  • In a phase IV study, 54% of patients taking Partner Therapeutics Inc.’s Leukine (sargramostim) plus standard of care (SOC) had an improvement in oxygenation of 33% or more from baseline compared to 26% of patients on SOC (p=0.0147).

Governments face future and fake vaccines

As biopharma companies remain focused on the research, government leaders continue to prepare for future pandemics, and battle those who attempt to exploit the current one.

U.S. President Joe Biden’s administration presented the America Rescue Plan, stressing the need for a large-scale national genomic surveillance system. Separately, a U.S. House Energy and Commerce Committee pandemic spending measure will provide $5.2 billion to the Department of Health and Human Services and $7.5 billion to the CDC. And biopharma executives argued before a U.S. congressional committee against a proposed intellectual property waiver for SARS-CoV-2 vaccines.

The European Commission is launching the Bio Defence Preparedness program to respond to the threat of new variants. The EU also is investing €225 million (US$270 million) to increase viral genome sequencing and research to 5% of positive cases across Europe. The effort may become part of a proposed Health Emergency Preparedness and Response Authority (HERA).

Finally, global leaders are struggling to control counterfeit or stolen vaccines, with 70 vials seized at a Columbian airport, Mexico pulling down nefarious websites selling fake vaccines, China arresting 80 people who produced more than 3,000 doses of fake vaccines, and the U.S. launching multiple operations, arrests and seizures.