Scientists around the world have emphasized that vaccines, along with therapeutic support, are the only effective tools to contain the ongoing COVID-19 pandemic. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causal agent of COVID-19. It is a highly contagious positive-sense RNA virus that has already claimed more than 3.3 million lives worldwide. At present, scientists are concerned about the emergence of SARS-CoV-2 variants and whether existing vaccines will remain effective against them. Hence, the development of robust therapeutic systems, such as repurposing drugs, could aid in managing the pandemic more efficiently. This article discusses the different vaccines and potential treatments developed thus far.
Progress in the development of COVID-19 vaccines and therapeutics
Scientists have developed or are in the process of developing different types of vaccines, which differ greatly in terms of their basic design. These vaccines could be DNA-based, mRNA-based, recombinant subunit, live-attenuated virus, inactivated whole-virus and viral vector or adenoviral.
On February 8, 2021, the World Health Organization (WHO) announced that at present seven different vaccines are being rolled out across several countries. Among the countries where the vaccination program has commenced, the vulnerable sections of the population are being given the highest priority for vaccination. At present, there are around 200 vaccine candidates that are being developed, out of which, more than 60 are undergoing clinical trials.
The University of Melbourne and Murdoch Children’s Research Institute, Australia in collaboration with Radboud University Medical Center, Netherlands, and Faustman Lab at Massachusetts General Hospital, USA, have developed a live-attenuated vaccine for COVID-19 called BCG. This vaccine is currently being investigated in a Phase 2/3 clinical trial in Australia, the Netherlands and the USA. Several vaccines have been developed which are based on an inactivated whole-virus, for example, BBV-152 by Bharat Biotech uses a whole inactivated virion of SARS-CoV-2. Another similar vaccine developed by Sinopharm and the Beijing Institute of Biological Products is BBIBP-CorV, which has received emergency authorization in China.
Companies such as Moderna, Inc., and Pfizer in collaboration with BioNTech, have developed an mRNA-based vaccine. mRNA vaccines work by introducing a short-lived synthetic fragment of mRNA – corresponding to a target protein (e.g., SARS-CoV-2’s spike (S) protein) – into an individual. The cells then use their own internal machinery to transcribe the mRNA and produce the antigen, triggering an immune response. Scientists believe that mRNA vaccines are a promising alternative to conventional vaccines due to their high potency, and the potential to include several mRNAs encoding multiple target proteins in a single vaccine, which is more challenging to achieve with traditional approaches. The Moderna and Pfizer–BioNTech COVID-19 vaccines have received emergency authorization from regulatory bodies such as the US Food and Drug Association (FDA) and Medicines & Healthcare products Regulatory Agency (MHRA). Both companies believe that this method of vaccine development is highly advantageous owing to its high efficiency, cost-effectiveness and rapid production possibility.
Accelerated Manufacturing of mRNA Vaccines
Accelerated timelines are critical when responding to an outbreak and efficient vaccine manufacturing is required to enable a quicker transition from research to the clinic, saving lives. mRNAs allow biotechnology companies to develop vaccines in response to pandemics, such as COVID-19, in a matter of weeks. Download this guide to learn more about how mRNA vaccines work, the benefits of mRNA capping and traditional vs novel capping methods.Download Guide
The third type of vaccine has been developed using an adenovirus vector, and has been used to inoculate millions of individuals across the world. ChAdOx1 nCoV-19 is an adenovirus vector vaccine that has been designed by Professor Sarah Gilbert and colleagues at the University of Oxford’s Jenner Institute, UK. The vaccine is being manufactured at a large scale by global biopharmaceutical giants, namely, AstraZeneca and Serum Institute of India. Another adenovirus vector-based vaccine has been developed by Johnson & Johnson, which has also received emergency authorization from several regulatory bodies across the world.
Scientists have also made some progress in developing therapeutics for the treatment of COVID-19. Therapeutics play a vital role in protecting COVID-19 patients, especially, in severely infected hospitalized cases. Drug repurposing, which involves the re-utilization of commercially approved drugs, helps to quickly identify molecular compounds for COVID-19 treatment.
At present, the FDA has approved remdesivir (Veklury®) for the treatment of SARS-CoV-2 infection while several therapeutic agents (antiviral drugs) are undergoing clinical trials. Remdesivir is an adenosine analog, which causes pre-mature termination of the nascent RNA virus. Chloroquine has also been reported to effectively inhibit SARS-CoV-2 infection. The mechanism by which chloroquine achieves this is by enhancing endosomal pH, which is required for virus–cell fusion, and also by interfering with the glycosylation of cellular receptors for SARS-CoV.
In 2003, ribavirin was extensively used to treat SARS patients with or without additional supporting drugs. Scientists have reported that ribavirin, in low doses, can be used to treat COVID-19. The low dosage would also help mitigate side effects. Additionally, ribavirin along with pegylated interferon could also trigger an innate antiviral reaction. Another drug that could be a potential candidate for COVID-19 treatment is favipiravir, which is an analog of guanine. Anti-HIV protease inhibitor lopinavir-ritonavir has also been reported to be effective against SARS-CoV-2 in both randomized clinical trials as well as non-human primate models. Additionally, researchers have proposed zuclopenthixol, nebivolol, and amodiaquine for early phase clinical trials.
Efficacy of COVID-19 vaccines and therapeutics – what do the experts say?
One of the most frequently asked questions is how long the vaccine will protect an individual from the disease. In the context of the Oxford–AstraZeneca (Vaxzevria) vaccine, Gilbert said, “Studies on the maintenance of immune responses are now underway. Work on other vaccines suggests that our vaccine may remain effective for over a year.” In terms of the efficacy of this vaccine across age groups, Gilbert also stated that “Efficacy does not appear to be reduced in older adults, but has not yet been determined in children, although studies on vaccine safety and immunogenicity in children are in progress.” While commenting on the need to vaccinate individuals who have recovered from COVID-19, Gilbert said that “This has not been determined as the clinical trials only reported on those who were seronegative for SARS-CoV-2 when vaccinated. However, in those who were seropositive when vaccinated, immune responses increased after vaccination.”
Different vaccines have shown different levels of efficacy. Dr Hanneke Schuitemaker, vice president and global head of viral vaccine discovery and translational medicine at Johnson & Johnson, has been an integral part of the vaccine developing team. According to Schuitemaker, “Topline results from our Phase 3 ENSEMBLE clinical trial showed that among all participants from different geographies and including those infected with viral variants, Janssen’s COVID-19 vaccine candidate was 66% effective overall in preventing moderate to severe COVID-19, 28 days after vaccination. The onset of protection was observed as early as day 14.” She further added that “the vaccine candidate was 85% effective overall in preventing severe disease across all regions studied and showed protection against COVID-19 related hospitalization and death beginning 28 days after vaccination.” However, the efficacy of this vaccine on seropositive individuals is still inconclusive. At present, all the biopharmaceutical companies are further assessing the efficacy of the vaccines against SARS-CoV-2 variants.
Andrew Leach, Head of Industry Partnerships and Head of Chemical Biology at EMBL’s European Bioinformatics Institute, Hinxton, UK, and Dr Anna Gaulton, ChEMBL Group Coordinator, are working, with their collaborators, to try and identify existing drugs that could be repurposed as new treatments for COVID-19. They said, “A number of treatments have been shown to be effective at reducing mortality and/or duration of hospital stay in rigorously conducted clinical trials.”
Leach and Gaulton highlighted several drugs with potential against COVID-19, which have been recognized by the UK and US regulators. For example, in the UK dexamethasone, remdesivir and tocilizumab are listed in the National Institute for Health and Care Excellence (NICE) COVID-19 rapid guideline. While in the US, the FDA has granted emergency use authorization for remdesivir, baricitinib (in combination with remdesivir) and two monoclonal antibody cocktails (casirivimab plus imdevimab, and bamlanivimab plus etesevimab).
According to the EMBL scientists, these therapies are broadly divided into antiviral drugs (such as remdesivir and monoclonal antibody therapies) that aim to tackle the SARS-CoV-2 infection and anti-inflammatory/immunomodulatory drugs (such as dexamethasone and tocilizumab) that aim to reduce the overactive immune response seen in severe COVID-19 cases. The scientists further pointed out that the best treatment strategy depends on the circumstances of each individual. “The most effective treatment regime clearly depends on the specific circumstances of each patient. What is clear is that well-conducted clinical trials (e.g., the RECOVERY trial that identified dexamethasone and the WHO Solidarity Therapeutics Trial) are critical in providing robust evidence to identify the most effective treatments,” concluded Leach and Gaulton.