There has been a large push to the development of a coronavirus vaccine and antiviral medicines. Having observed promising premises for an effective vaccine, researchers are “cautiously optimistic” about its clinical launch. A widespread vaccine deployment within 1-2 years would effectively end the COVID-19 pandemic, as per the emerging scientific advances from the US and other countries. Dr D Samba Reddy, Professor, College of Medicine Texas A&M University Health Science Center, USA, explains how developments for a new vaccine and repurposed antiviral medicines can help combat the coronavirus crisis
The coronavirus pandemic has created huge challenges in our daily lives and great uncertainty worldwide. Our working environments, education, family lives, business and financial prosperity, and daily routines have been reshaped significantly, perhaps even permanently. The coronavirus disease 2019 (COVID-19) outbreak urgently requires new medicines for prevention and treatment. The 3-15 per cent mortality rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the strain of the virus that causes COVID-19, ranks as one of the deadliest respiratory viruses, especially in aged and vulnerable people with health risk conditions. To date, this virus has infected more than 11 million people and killed over 525,000 worldwide. Currently, there are no effective, US FDA-approved agents for the prevention and treatment of COVID-19.
Given the steady emergence of positive cases even under social distancing and extended lockdowns, many are desperately awaiting a vaccine or “silver bullet” treatment for COVID-19. Despite great mitigation efforts and huge economic sacrifices, the virus is asynchronously circulating in many countries including India, which is currently experiencing a rapid surge. Now, the US is experiencing a coronavirus resurgence; the number of daily new COVID-19 cases is hitting levels not seen since the early part of the pandemic. This virus is spreading in large part from asymptomatic persons who have been unknowing carriers. Two questions that frequently appear in many people’s minds are how long they should practise social distancing measures and when this pandemic situation will return to normalcy. For both questions, a vaccine would be our most concrete answer for preventing future infection and ultimately totally eradicating the coronavirus outbreak.
To fight this battle of a lifetime, scientists around the world are making rapid progress in the discovery of two types of medicines for coronavirus: vaccines to prevent the infection and antivirals to treat the infection. It normally takes 5 to 10 years to develop a vaccine or new drug, but due to the urgency of the COVID-19 pandemic, normal development activity and testing have been accelerated with some caveats.
A vaccine would be our most concrete answer
Vaccines are biological agents with a potential for immunological reactions or efficacy issues. They require extensive testing and safety trials –the bottleneck in development time− along with tedious production and scale-up for producing millions of doses of a formulated injectable product with optimal stability. Many top experts predict a COVID-19 vaccine could take 6-18 months to reach the market.
Currently, there are approximately 160 corona vaccines in development. These vaccines are being tested in ongoing clinical trials to prove their safety and effectiveness. Constantly-updated knowledge about virus strains and the science underlying neutralizing antibodies has provided a number of potential vaccine platforms or antigen components, such as the purified spike protein, envelope protein, recombinant viral vectors expressing the spike or other viral protein, RNA packaged within a vector such as lipid nanoparticles, and killed or inactivated virus particles. Immunization with these injectable components can produce high levels of neutralizing antibodies and protect against detrimental infection after exposure to the virus.
A realistic timeline for development and widespread vaccination
Currently, three vaccines have reached Phase 2 and would enter pivotal Phase 3 trials this summer. This timetable indicates rapid progress in advancing vaccines through clinical testing. The main hurdle for these solutions is proof-of-efficacy: the trials must demonstrate with certainty whether people who receive the vaccines develop COVID-19 after viral exposure at lower rates than those who get placebo or dummy injections. Successful clinical trials would eventually lead to the FDA approval of a vaccine. FDA approval represents the final phase of a bench-to-bedside journey for any new vaccine— a long journey that begins within vitro or test tube studies to animal testing and clinical phase 1−3 trials. When its data demonstrates proof of safety and efficacy, the vaccine can earn FDA approval for marketing. Yet, there remain some uneasy questions regarding this process, particularly the possibility that a coronavirus vaccine is delayed or hits a roadblock. However, some solid research theory provides hope in light of such concerns.
As noted by NIH Director Dr Francis Collins in his blog, research has shown that patients who recover from COVID-19 produce small levels of antibodies to the virus, some of which are strongly neutralising, which indicates that some patients may be able to ward off reinfection. This premise suggests that the immune systems of people who survive COVID-19 may be primed to recognise SARS-CoV-2 and possibly thwart a second infection, which supports the potential feasibility of antibody-based vaccination. Regarding the durability of such a vaccine, the neutralising antibodies against SARS-CoV-2 are projected to last 15-18 months, based on the duration of antibody responses against other human coronaviruses. The lessons learned from SARS and MERS underscores the current vaccine approaches to the prevention of COVID-19.
Despite the potential viability of a vaccine for COVID-19, researchers remain “cautiously optimistic” about its efficacy and timeline, considering the hurdles yet to be overcome. Currently, in a global search for a COVID-19 vaccine, no clear “winner” has emerged yet. When a safe and effective corona vaccine is approved, a widespread vaccine deployment within 1-2 years will effectively end the COVID-19 crisis, as per the emerging scientific advances from the US. An international consortium is needed to coordinate such large-scale production and distribution around the globe. Thus, current projections indicate that the coronavirus pandemic will continue for 1-2 years, a critical timeline for development, deployment, and widespread vaccination.
Besides vaccines, there have been dedicated efforts to develop other pharmaceutical options for coronavirus, namely antivirals and immune modulators, some of which are now in clinical trials or have been approved for COVID-19.
The current race for repurposed antiviral medicines
Antivirals are medicines that act directly on coronavirus. The main advantage of an antiviral agent is that it can be given to treat asymptomatic person already infected with the coronavirus. Most antivirals are made of small molecules that can be synthesised in the lab and tested much faster than vaccines. In contrast to a vaccine that prevents infection, antivirals act more like bandages: they can alleviate the recovery and reduce the severity or risk of morbidity, but cannot prevent an infection from happening.
There are many antivirals under experimental and clinical trials for coronavirus infection. According to the University of Pennsylvania’s CORONA database, 115 repurposed drugs have been used to treat COVID19 patients, with around a dozen which seem most promising. Like vaccines, FDA approval of antivirals represents the final phase of a big development journey from preclinical to clinical phase 1, 2 and 3 trials. When the data demonstrate compelling proof of safety and efficacy or favourable risk-benefit ratio, such new medicines can receive FDA approval for marketing. To address urgent needs, the FDA has granted emergency use authorization (EUA) for clinical testing and compassionate use of certain medicines for COVID-19, bypassing typical time- and sample-related roadblocks. This is helping scientists more quickly test existing drugs, and such repurposing is offering great hope in our COVID-19 fight. Some of the more notable explored treatments are detailed below.
Chloroquine and hydroxychloroquine (HCQ) have been proposed as new treatments for COVID-19. They have broad-spectrum effects against coronaviruses via multimodal mechanisms. Additionally, millions of people have safely used these medicines for malaria worldwide; however, they are not indicated in certain people with cardiac risk factors. Based on early positive indications of its benefits from pilot trials in China, chloroquine has been used for the treatment of COVID-19 in clinical trials or emergency use programs. HCQ, a safer version of chloroquine, is on the WHO’s list of essential medicines − a designation given for the safest and most effective medicines needed in a healthcare system. Based on reports of its antiviral effect against the coronavirus, HCQ was granted EUA status for use against COVID-19 by the FDA on April 7. It was tested as a specific treatment in the hospital setting and in clinical trials. Later, the Indian ICMR recommended HCQ as a prophylactic for healthcare personnel.
However, the safety of HCQ in COVID-19 patients is a topic of controversy, stemming from a scandal regarding the retraction of two papers about the negative safety of HCQ published in the top-ranked medical journals Lancet and NEJM. The retractions occurred on account of a lack of data integrity, making safety claims of HCQ still inconclusive. Additionally, the results of recent clinical trials show limited efficacy of HCQ therapy in COVID-19 patients. Therefore, the WHO and NIH have pulled out of HCQ trials due to questionable efficacy that has greatly diminished further interest in this drug. Effective June 22, the sponsoring company made the decision to stop and discontinue its sponsored HCQ clinical trial for COVID-19. They did not cite safety reasons. On June 15, the FDA revoked the EUA for emergency use of chloroquine and HCQ for COVID-19. As of June 25, the NIH treatment guidelines recommend against the use of chloroquine or HCQ for the treatment of COVID-19, except in a clinical trial.
Remdesivir is another repurposed antiviral drug with promising effects on coronavirus. It inhibits a viral protein called RNA-dependent RNA polymerase, which is vital for virus production. It has potent in vitro inhibitory activity against SARS-CoV-2. In real-world practice, however, it has shown mixed results. In early trials published in Lancet, remdesivir was not associated with clinical benefits in patients with severe COVID-19. On March 1, the FDA granted an EUA for emergency treatment of hospitalized patients with severe COVID-19. On April 29, in results from a pilot trial sponsored by the NIH, remdesivir was found to shorten the duration of illness by about 31% compared to placebo in hospitalised patients with severe COVID‑19. The data, now published in the New England Journal of Medicine, show that the drug shortened the course of illness from an average of 15 days to about 11 days. However, mortality rates were not significantly different (7 per cent drug vs 12 per cent placebo), indicating that remdesivir alone is not likely to be sufficient.
Currently, remdesivir is being tested in Phase 3 trials for severe infection, but it is not FDA-approved yet. It is given by intravenous infusion for up to a 10-day total course. On June 1, some early Phase 3 trial results became available, which indicated it has only small benefit in large samples. In this large trial, a group of moderately ill, hospitalized patients with 5-days therapy showed a modest improvement (76 per cent) compared to standard-of-care control (66 per cent). The other group on 10-days therapy did not show any significant improvement. There were no new safety risks identified in either group. Remdesivir is also only available intravenously, meaning it is only able to be administered in a clinical setting, which could limit its impact for ambulatory patients and persons staying at home with mild symptoms. So, the results of ongoing pivotal trials will determine its capacity for use against COVID-19.
The NIH treatment guidelines recommend the investigational new drug remdesivir for hospitalised patients with severe COVID-19. Those who are not intubated are to receive 5 days of remdesivir, while for mechanically ventilated patients or patients who have not shown improvement after 5 days of therapy, the treatment can be extended to up to 10 days. Remdesivir is not recommended for the treatment of patients with mild or moderate COVID-19.
Other promising antivirals for COVID-19 include protease inhibitors (Lopinavir, Ritonavir), RNA polymerase inhibitors (Ribavirin, Favipiravir), viral fusion inhibitors (Arbidol), viral receptor entry inhibitors (Camostat), and anti-parasitic agents (Ivermectin). However, most of them are still in clinical trials. To accelerate trials and identify an effective drug, the WHO is coordinating an international Solidarity trial of the most promising antivirals for COVID-19, including Remdesivir, Lopinavir, Ritonavir and others.
On June 20, the Drugs Controller General of India (DCGI), the national drug regulation authority, approved the antiviral drug Favipiravir for the treatment of mild to moderate COVID-19. In a landmark development, an Indian generic pharma company received the approval for manufacturing and marketing of Favipiravir. Now, Favipiravir has become the first approved oral medication for the treatment of COVID-19 in India. Favipiravir, known for treating influenza in Japan, has a unique mechanism of action against the coronavirus. First, it is converted into an active phosphoribosylated form in host cells and serves as a substrate for viral RNA polymerase. Then, it inhibits the viral RNA polymerase, a key protein for viral replication in the body. In India, Favipiravir is available as prescription tablets for a 14-day therapy for mild to moderate infection. It offers broad coverage, including children, adults, the elderly, and people with health conditions. It is claimed to significantly improve symptoms in mild to moderate COVID-19 patients. Presently, it is still undertrials in the USA and other countries and not yet approved by the FDA for the treatment of COVID-19.
The hype about new antivirals needs to be verified by large, randomized trials or future meta-analysis. Some caution should be exercised on the boon of new antivirals, as we have learned harsh lessons from previous antivirals. The launching of generic versions of remdesivir and favipiravir is a highly positive development for supportive treatment. Yet, the results of ongoing or pivotal trials will decide the potential of these and other antivirals for COVID-19.
Immunity boosters as critical adjunct medicines for survival
Another class of treatment known as Immunity modulators have been proposed as adjunct therapies for symptomatic management of COVID-19, especially for at-risk populations (elderly, immunocompromised, very young, people with certain health conditions). Currently, there are no FDA-approved immunity boosters. Some experimental agents include interferons, cytokine inhibitors or monoclonal antibodies (Tacosilizumab, Sarilumab), and immunoglobulins. They are targeted to control the heightened immune response in COVID-19, principally to check the “cytokine storm,” a state of uncontrolled inflammation that can damage vital organs. Hence, anticytokines are considered as an alternative for combination therapy with antivirals. Tocilizumab, an injectable monoclonal antibody for use in autoimmune diseases such as rheumatoid arthritis, has shown in early trials to dampen the cytokine response in COVID-19 patients.
The WHO advisory says that corticosteroids, which suppress the immune response and cytokine storm, should not be used as they could delay recovery or increase morbidity. However, a recent study shows some benefits of dexamethasone in severely ill patients. Dexamethasone is the first drug to be shown to improve survival in severe COVID-19 patients. However, it did not appear to help mild or moderately infected patients. Consequently, the NIH guidelines panel recommends using dexamethasone (6 mg daily for up to 10 days) in patients with COVID-19 who are mechanically ventilated and in patients who require supplemental oxygen. Similar to the WHO, they recommend against using dexamethasone in patients with COVID-19 who do not require supplemental oxygen. There are insufficient data for the NIH panel to recommend either for or against any other immunomodulatory therapy in patients with severe COVID-19 disease. In patients with COVID-19 and severe or critical illness, there are insufficient data to recommend empiric broad-spectrum antimicrobial therapy in the absence of another indication.
Plasma therapy works
Plasma therapy or convalescent plasma has proven effective in reducing the severity or mortality of corona infection. In such immunoglobulin therapy, the liquid portion of the blood that has antibodies from recovered patients is given to patients with severe COVID-19. Although plasma therapy may help accelerate recovery, limited donor availability may limit the widespread use of the convalescent plasma.
A BCG vaccine is touted to reduce the impact of COVID-19 because it has beneficial nonspecific (off-target) effects strengthening the immune system and thereby reducing viremia after coronavirus exposure. A trial is underway to study if BCG vaccine can strengthen immune response, with consequent less severe infection or rapid recovery.
Some vitamins and nutraceuticals have been claimed to help against coronavirus infection. Currently, there is a lack of systematic studies evaluating these supplements in COVID-19 patients.
Stem cells are also touted as promising immune boosters to combat COVID-19, especially for critically ill patients. Stem cells are thought to slow down the immune response and prevent the body from damaging itself from cytokine storm. Such therapy is not yet proven effective or safe, so has not been approved for the treatment of COVID-19.
Herd immunity is a natural catastrophe
Herd immunity, while not touted as a solution for COVID-19 by any agency, is a natural process relevant when there are a massive surge and widespread hotspots in a town or city. Herd immunity is reached when the majority of a given population −70 to 90%− becomes immune to the virus, either by recovery from infection or through vaccination. In that scenario, the virus does not spread to people who are not immune due to a lack of carriers. At its worst, catastrophic hotspots may have to rely on herd immunity if a vaccine is still not available in a timely fashion. However, how long immunity lasts varies depending on the coronavirus, and it is not yet known how long COVID-19 survivors might have that protection.
In the US, India, Brazil, and many other countries, there has been a rapid surge or resurgence of cases. About 40% of cases are asymptomatic, which may be driving the community spread. Besides social distance measures, widespread testing and isolation are critical steps in containing the virus. Pool testing could find asymptomatic persons quickly by strategically testing groups of people together. It could test more people with fewer tests in a much broader net and positive cases could be quickly isolated. Meanwhile, scientific experts are advising for the traditional mitigation tools–identify, isolate and contact trace– for curbing the spread and flattening the infection curve.
We will ultimately prevail
At this time, we should continue to follow the scientific guidelines for surviving the coronavirus pandemic. The primary mode of transmission is the airborne route. Infected persons, both asymptomatic and symptomatic, have the great potential to generate aerosol (from sneezing, cough, breathing or talking) in size ranges that can remain suspended in air and be inhaled by others. Confining aerosols as close as possible to their point of generation is the first critical step in the standard healthcare protocol. Aerosols represent a risk of both inhalation and contamination of surfaces, clothing, and objects. Hence, confining aerosols through masks and hand washing reduces the extent of contamination and minimises the potential exposure opportunities.
The ultimate goal of public health advisories and mitigation strategies (eg, social distancing, mask-wearing, good hygiene) is to reduce the risk of acquiring an infection and of spreading the virus onto others. It is a personal responsibility to adhere to safe practises at home, in the workplace, and outside. Maintaining mindfulness during daily interactions is critical to accomplish the two basic principles of biosafety: risk assessment and containment. To put this complex science into common awareness, strive to follow two essential practices: (a) avoid potential sources of exposure to the virus as much as possible; and (b) maintain general wellness (ie, food, sleep, light exercise), a preemptive step to combat the corona disease.
In summary, the US FDA to date has approved no therapies for coronavirus. COVID-19 pandemic is an unprecedented challenge for millions of people worldwide. Thus, aside from new diagnostic tests such as pool testing, development of novel antivirals and vaccines will remain the highest-priority scientific research for the next few years. There is cautious optimism about a coronavirus vaccine, but it is too early to make concrete judgments. In the meantime, the two best ways to prevent coronavirus infection are to limit potential exposure and strengthen our health and immunity. It may even take a couple of years, but we will ultimately prevail.
Disclaimer: The author, Prof Samba Reddy, is a reputed medical scientist in Texas, USA. He works at Texas A&M University. The views expressed are those of the author and do not necessarily represent the views of any organisation with which he is affiliated. He provides healthcare talks and Q&A sessions on coronavirus.
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