A huge amount of work and investment has gone into the development of diagnostics, new treatments, and vaccines to combat COVID-19. There is also an unparalleled level of collaboration at all levels that will be critical to achieving success in our fight against the pandemic. Hopefully, these collaborations, along with regional and global coordination efforts, will deepen and expand as we move into the next phase of the pandemic.

Vaccine R&D has taken a major step forward with the recent announcements from Pfizer/BioNTech and Moderna that their mRNA-based vaccines have shown greater than 90% protective efficacy in late-stage clinical trials. That’s hugely encouraging news and is a big relief to everybody who works in the field. In their own way, they have also further raised the expectations of what vaccines can achieve, which needs to be managed.

At the moment, there are approximately 50 vaccine candidates in clinical trials in humans, 10 or 11 of which are at late-stage phase 3. It’s important to have many manufacturers and platforms, because we still have very little evidence or data on how different vaccines behave in different target populations. Even if all those vaccines in late-stage development should prove effective in the next few months, there are still big hurdles to overcome in terms of regulatory requirements, upscaling of manufacturing, supply of vaccine components and raw materials, and the pure logistics, distribution, and delivery of the vaccination programs nationally and globally.

The fact that most of the vaccines require two doses is an added complexity because if patients are required to come back for a second dose three to four weeks later, it needs to be the same vaccine. Based on current evidence, we can’t recommend mixing different vaccines. There are warnings about overinterpreting the high efficacy rates in clinical trials, and we don’t know, for example, what the protective efficacy is after just one dose. Efficacy in these trials has been measured at the optimal time period, so seven days after the second dose. It’s likely to be less than 95% when it’s actually rolled out in mass vaccination programs.

Another unknown factor is that, unlike influenza, we don’t know yet how coronavirus will behave or what will happen when a significant portion of the population becomes immune, either through previous infection or vaccination. The virus hasn’t had very much resistance up to now — it’s spread quickly and easily. The selective pressure for mutations may change once it gets up to 30% to 50% of the population immunized. One complicating factor with coronavirus is that it jumps quite easily between species. That’s always a worrying sign, because during that process it tends to mutate, like it did in Denmark at mink farms.

When vaccine manufacturing and distribution starts, deliveries will be either weekly or biweekly. Looking at the current projections by major manufacturers, they’ll reach somewhere in the region of 7 to 8 billion doses if all goes well by the end of 2021. Consequently, demand will exceed supply until the end of 2021 or even 2022 at least.

No COVID Therapeutics in Sight

That’s why it’s so unfortunate that results around treatments or therapeutics have not been very encouraging so far. There is a clear and urgent medical need for new therapeutic options to reduce the severity and the mortality from COVID in hospitalized patients. But the only drug so far that’s shown clear clinical benefit is the old corticosteroid dexamethasone, the effect of which is to reduce the immune response and the cytokine cascade seen in severely ill patients.

The search for drugs against COVID has focused on three main approaches: to prevent virus entry into the cells; to find direct acting antivirals, which interfere with the replication of the virus and actually kill it inside the cells; and to look for immunomodulators to dampen the immune response. The rationale for these approaches is that we recognize COVID as a biphasic disease. Following an incubation period of about five to seven days after infection with the SARS-CoV-2 virus will be the acute viral phase. It’s a period of intense viral replication in the respiratory tract, which will cause local damage and some local inflammation. This will lead first to flulike symptoms, including aches and pains, fever, and cough. Most patients will experience a range of symptoms, but usually recover within seven to 10 days.

But a small group of patients go on to develop much more severe disease, what’s known as a hypoxemic respiratory failure or acute respiratory distress. This is immunopathologically driven. These patients experience a severe inflammatory response due to cytokine release syndrome. Looking at blood pictures, their inflammatory markers are greatly abnormal, including IL-6, ferritin, and C-reactive protein. It’s thought to be driven mainly by an abnormal immune response in the body, which is partly driven by virus replication, because these patients will usually have prolonged virus excretion. Obviously, this leads to problems with oxygen uptake, which leads to hypoxemic respiratory failure and organ damage.

Drugs That Prevent Entry

There have been two ways to prevent the virus from entering or infecting the cells. One approach is by blocking the binding of virus to the receptors or interactions of the virus at the cellular level with several of their receptors. For example, ACE/Angiotensin II receptors, where a number of drugs to block these receptors that initially have been developed to control blood pressure are available. But this also happens to be the receptor complex through which the virus enters the cells. The other type of receptors that people have been looking at are the CCR5 receptors, which are involved in the fusion process. Those have been targeted, for example, for HIV and influenza. The drug Maraviroc (Sandoz) is undergoing studies to see if it can be used against SARS-COV-2.

The other approach to prevent virus infecting cells is to use convalescent serum to neutralize the virus or monoclonal antibodies that are specifically directed against the spike protein of the virus. This is known as passive immunization, a well-established concept to prevent and treat some bacterial and viral infections. Two of the drugs that have generated the most interest here are Regeneron’s mixture of two monoclonal antibodies, which has been shown to have some effect in nonhospitalized patients, and Eli Lilly’s Bamlanivimab, which has an emergency use authorization for mild COVID. But neither of these two preparations has shown any promise to treat hospitalized patients, so it’s used before patients require hospital treatment or oxygen supplement. There is a fear that treatment of severe patients could exacerbate or worsen the symptoms in these patients.

Direct-Acting Antivirals

The direct-acting antivirals interfere with virus replication and kill the virus inside the cells. These are mainly repurposed drugs, broad-spectrum antivirals that have been developed against other RNA viruses such as HIV, HCV, influenza, Zika, or Ebola. Most of them target a unique enzyme found only in RNA viruses. There are currently four drugs in development that have generated the most interest. Favipiravir, by Avigan, is authorized in Japan, China, and Russia for the treatment of influenza and coronavirus. It’s not registered in the U.S., EU, or the UK mainly because there is animal data showing that it may have some teratogenic effects. Galidesivir, by BioCryst, is a BARDA-sponsored drug under development. Molnupiravir, by MSD, is currently the most advanced in clinical development — in phase 2b/3 studies. Of course, there’s Remdesivir, by Gilead, and the early studies from the ACTT-1 trial looked quite promising. But the results with the final analysis were at best modest. A big WHO study (Solidarity) showed that it does not have any effect on hospitalized patients in terms of reducing mortality, need for oxygenation, or duration of illness. The jury is still out on whether there’s a use for this antiviral or any therapeutic effect in hospitalized patients.

The focus up to now with these antiviral drugs has been on looking at hospitalized patients in clinical trials, which we know from previous experience is problematic. For example, we have three well-known and widely used antivirals against influenza: Tamiflu, Zanamivir, and Peramivir. But all three have failed phase three studies in hospitalized patients. Even today, there is no influenza drug approved for the treatment of severe influenza. Part of the reason is the difficulty in carrying out those kinds of efficacy studies, with the endpoints and the diversity of the patient population, to demonstrate effectiveness in these patients. The experience that we had with influenza that will also be borne out with coronavirus is that treatment needs to start early, within the first two or three days after symptoms, for the drug to be effective.

So as with influenza, we may need to start rethinking about focusing attention with these drugs on post-exposure prophylaxis, to be used, for example, in conjunction with vaccines, to control outbreaks going forward.

Immunomodulators

The third group of therapeutics that have been looked at to treat COVID are the immunomodulators, dampening the cytokine inflammatory response. There’s been a lot of effort looking at the cytokine-dampening monoclonal antibodies. They were initially mainly developed to treat inflammatory conditions such as rheumatoid arthritis. But there have been, up to now, disappointing results. The attention now is focusing more on another cytokine called granulocyte macrophage colony stimulating factor, GMCSF, which is thought to be important in the hyper-inflammatory state in some COVID patients. Several monoclonal antibodies are being investigated.

Despite huge efforts going into finding treatments for hospitalized patients, we still have very few options to combat severe COVID, and that will be the top priority to reduce mortality and severity in COVID patients. The other thing is that most of these drugs are in early-stage development, so they won’t read out until quarter one, quarter two next year, and we haven’t yet seen the clinical trial protocols for the type of phase three studies we would need to actually get products on the market in the near term.

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About Dr. Hillar Kangro

Dr. Hillar Kangro, PhD, is an independent consultant, pathologist/epidemiologist, and pharma executive with over 25 years of experience both in academic public health and industry settings. He is the former Medical/Scientific Director for Infectious Diseases at GlaxoSmithKline, where he oversaw a portfolio of vaccines and anti-infectives intended for emergency use and preparedness, including pandemics, bioterrorism, and antimicrobial resistance.

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This article is adapted from the November 18, 2020, GLG Teleconference “Vaccines and Antivirals for COVID-19.” If you would like access to this teleconference or would like to speak with Dr. Hillar Kangro or any of our more than 700,000 experts, contact us.