February 25, 2021 -- Despite the small number of COVID-19 vaccines that have been granted emergency use authorizations (EUAs) by the U.S. Food and Drug Administration (FDA) to date, many biopharmaceutical companies are continuing to push new vaccine candidates toward regulatory approval. The slow rollout of approved vaccines has created the need for second-generation products with the potential to accelerate the world's return to something approaching normalcy.
What we have now
To briefly summarize, messenger RNA (mRNA)-based vaccines produced by Moderna and Pfizer and BioNTech were granted EUAs in late 2020 in the U.S. and are currently in use in several additional countries and regions around the globe. Most recently, the University of Oxford's modified chimpanzee adenovirus-based vector vaccine was granted an emergency use listing (EUL) by the World Health Organization (WHO) on February 15 and is currently in use in several countries including the U.K. and in South America.
A single-dose vaccine candidate produced by Janssen leveraging the company's AdVac viral vector vaccine platform is likely to be the next product to reach regulatory approval in many regions. The company is holding its committee meeting to discuss a possible EUA submission on February 26. Based on briefing documents, the agency is likely to issue the emergency approval rapidly following the meeting. The company has also submitted for conditional marketing authorization (CMA) to the European Medicines Agency (EMA) and EUL with the WHO.
Importantly, all of these products are undergoing rigorous clinical testing -- both in vitro and postmarket approval -- to evaluate efficacy against emerging SARS-CoV-2 variants. The companies also are starting testing on important patient populations, including pregnant women and individuals with cancer.
In the clinical pipeline
There are currently 248 COVID-19 vaccines under development, falling into nine different platform categories. Of these, 56 candidates are actively being evaluated in clinical trials. Here is a closer look at some of the front-runner second-generation COVID-19 vaccines.
Novavax announced on January 28 that NVX-CoV2373, its protein subunit-based COVID-19 vaccine candidate, met the primary end point, with a vaccine efficacy of 89.3% in its phase III clinical trial conducted in the U.K. This protein subunit vaccine uses the full-length SARS-CoV-2 glycoprotein encapsulated in nanoparticles and adjuvanted with the company's Matrix-M adjuvant to provoke an immune response.
In December, Inovio began a phase II segment of a phase II/III clinical trial funded by the U.S. Department of Defense to test its DNA-based vaccine candidate, INO-4800, delivered via intradermal injection with the company's Cellectra device. Inovio said its candidate offers a long shelf life and heat-tolerance. INO-4800 is composed of synthetic, circular DNA plasmids that encode parts of the viral protein.
After delays in clinical testing in December 2020, Sanofi and Glaxo Smith Kline (GSK) initiated a phase II study of their adjuvanted recombinant protein subunit-based COVID-19 vaccine program in February 2021. The vaccine is intended to improve immune response in the elderly. Phase I/II interim results showed an insufficient immune response in older adults, which demonstrated the need to refine the concentration of the antigen to provide a high-level immune response across all age groups. The new phase II study will enroll 720 individuals to select the appropriate dosage of an improved antigen formulation. A phase III study is expected to begin in the third quarter of 2021. The candidate is stable and can be refrigerated at normal temperatures.
Valneva and Dynavax are developing VLA2001, a vero-cell-based, highly purified inactivated vaccine candidate against SARS-CoV-2. VLA2001 consists of inactivated whole-virus particles of SARS-CoV-2 with high spike-protein density, combined with two adjuvants, alum and CpG 1018, Dynavax's proprietary toll-like receptor 9 (TLR9) agonist adjuvant. Valneva has an agreement in principle with the U.K. government to provide up to 100 million doses of its vaccine, which will be produced in Scotland. Valneva initiated a phase I/II clinical study in December 2020, evaluating the safety and immunogenicity for three dose levels in approximately 150 healthy adults.
Codagenix and Serum Institute of India have initiated dosing in a phase I trial of their COVI-Vac, a single dose, intranasal, live attenuated vaccine. A randomized, double-blinded, placebo-controlled dose-escalation study, the trial is evaluating 48 volunteers at multiple dose levels to determine safety and tolerability. Also, the study will evaluate the vaccine's ability to provoke an immune response -- measuring neutralizing antibodies, mucosal immunity in the airway, and cellular immunity.
In late January, Regeneron reported positive interim data for its Regen-CoV antibody cocktail used as a passive COVID-19 vaccine. In passive immunization, antibodies against an infectious agent are administered directly. Confirmatory phase III results are expected early in the second quarter. The candidate targets those patients who need immediate protection or who respond poorly to vaccination.
On the horizon
Gritstone Oncology is advancing development of its vaccine against SARS-CoV-2 with potential for both prolonged protection and potency against spike mutants. Gritstone and the U.S. National Institute of Allergy and Infectious Diseases (NIAID) have entered into a clinical trial agreement to initiate clinical testing. A phase I trial, expected to be conducted through the NIAID-supported Infectious Diseases Clinical Research Consortium (IDCRC), is being planned.
Through a license with the La Jolla Institute for Immunology, Gritstone has access to validated SARS-CoV-2 epitopes, which it uses along with the company's proprietary Gritstone Edge and vaccine platform technologies. It is developing a vaccine, containing the spike protein, similar to first-generation vaccines, but also additional viral epitopes that offer good targets for T-cell immunity. Gritstone uses self-amplifying mRNA and adenoviral vectors to deliver the SARS-CoV-2 viral antigens. The vaccine may have pan-SARS/coronavirus potential to protect against future coronavirus pandemics.
In December, OSE Immunotherapeutics announced it obtained $6.3 million for the clinical development of CoVepiT, its second-generation COVID-19 vaccine. A human clinical trial is expected to start in the first quarter of 2021. The candidate is reported to target 11 virus proteins to prepare for potential mutations.
In early January, Akston Biosciences and LakePharma, a contract research, development, and manufacturing organization (CRDMO), established a strategic partnership. LakePharma will manufacture commercial quantities of Akston's adjuvated COVID-19 vaccine candidate, AKS-452, which is scheduled to begin phase I/II clinical testing soon.
AKS-452 is a COVID-19-specific fragment crystallizable (Fc) fusion protein vaccine engineered to induce or boost a T helper cell 1 (Th1)/Th2 mixed immune response in patients against the receptor-binding domain of the SARS-CoV-2 spike protein. AKS-452 has been shown to be shelf-stable for weeks at up to 37° C, simplifying distribution and avoiding costly cold-chain transportation issues.
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