Promising COVID-19 treatments and vaccines; light at end of the tunnel

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Promising COVID-19 treatments and vaccines; light at end of the tunnel

Dr Paul Edwards & Dr Ernest Madu

Sunday, August 02, 2020

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With the outbreak of the SARS-CoV-2 virus and the subsequent COVID-19 disease epidemic, measures such as mask-wearing, social distancing and hand washing have been effective in halting/slowing virus spread. In contrast to many other infectious agents, we have not had drug therapy to treat acute infection or vaccines to prevent the spread of the virus throughout society.

The past one to two months have seen some promising developments in potential treatments for COVID-19 disease and several candidates for vaccines that may be available in a shorter time frame than was initially thought. This week we will look at the current state of affairs regarding treatments and potential vaccines in the horizon.

Treatment: Remdesivir

Remdesivir is an antiviral drug, that is, it inhibits the multiplication of viral agents. The drug was first developed in 2014 as a treatment for the Ebola virus. The drug has been known to have efficacy against the coronavirus family including the SARS-CoV-1 virus and the MERS virus. Given this history it was one of the earliest antiviral agents that was used to treat patients with COVID-19 disease. The drug must be injected into the bloodstream and is converted into a form that enters the cells. It acts by interfering with the multiplication of the SARS-CoV-2 virus. The initial experience with this drug was with small trials in China. However, more promising data was obtained from a worldwide trial sponsored by the National Institutes of Health (NIH), USA. This study looked at approximately 1,077 people in 60 sites across the world.

The patient population studied had COVID-19 disease with evidence of pneumonia. In the patients who were given Remdesivir, the time to recovery was shortened to 11 days compared to a recovery period of 15 days in those treated with placebo. This study did not suggest that Remdesivir decreased the chance of dying. Based on this finding, Remdesivir has been approved for the treatment of severe COVID-19 disease in hospitalised patients in both the United States and Europe. The drug is still considered investigational with further information needed on long-term safety. More recently, Gilead Sciences (the company that manufactures the drug) has released further data at a virtual COVID-19 conference.

The press release alludes to Remdesivir lowering the risk of dying and being effective in the pregnant and paediatric populations. This data, however, has not yet been submitted to outside peer review. Gilead Sciences has also announced a small trial of 60 patients looking at the possibility of an inhaled version of the drug, which could allow outpatient treatment. Our checks with local pharmacies in Jamaica suggest that this potentially life-saving medication is currently not available in Jamaica. We will encourage the Ministry of Health to reallocate some funds as a matter of national priority to procure a stockpile of this medication in Jamaica if we experience a surge in COVID-19 infections.

Treatment: Dexamethasone

From the early stages of the COVID-19 epidemic, it has been clear the immune activation or dysregulation plays an important role in the disease process particularly in the damage that takes place in lung tissue. Steroid medications (of which dexamethasone is one example) are thought to modulate immune responses and thus reduce the chance of lung injury. In June, physicians from Oxford University reported on their experience in patients hospitalised with COVID-19 disease in nine United Kingdom hospitals. The population of patients studied comprised approximately 6,500 patients. In this population, patients that had a need for respiratory system support (on a mechanical ventilator or had the need for oxygen) were found to benefit from dexamethasone.

Patients on ventilators who received dexamethasone had a 35 per cent reduction in the risk of dying. Patients who needed oxygen only (not intubated) had a 20 per cent reduction in the risk of dying. Patients who did not need respiratory support did not appear to benefit from dexamethasone — a widely available drug, as it has been in use for many years for multiple conditions. We must, however, review our national stockpile and ensure that there is enough dexamethasone in the island and that supply chains for additional supplies are secured ahead of any potential surge.

Treatment: Interferon

Interferons are chemicals in the body that play an important role in the body's immune response to inflammation and infection. Studies in patients with coronavirus infection have suggested that the SARS-CoV-2 virus block the natural interferon response. This results in infected cells being unable to chemically warn adjacent cells of invading virus particles and thus increases susceptibility to viral infection. Interferons have been used in the treatment of viral infections including hepatitis C and immune-mediated conditions such as multiple sclerosis. A small study of 100 patients at nine United Kingdom hospitals was performed. In this study, inhaled interferon-beta was found to reduce the risk of being on a mechanical ventilator or death by 79 per cent. Given the relatively small numbers of patients a larger study is needed to confirm the results.

Vaccines

An important part of the strategy for return to normal life is the development of a safe and effective vaccine to the SARS-CoV-2 virus. Over the past month there are indications that vaccine development is proceeding rapidly. It is estimated that worldwide there are approximately 200 candidate vaccines in development with 23 in clinical testing. As we have discussed previously, vaccine development proceeds in stages. Usually animal testing is performed before human studies. Human testing is usually divided into three stages: Phase 1, which is usually done in a small number of people to find a safe effective dose; A Phase 2 study usually involves a larger group of people with characteristics of the target population. Efficacy (which is usually defined as immune response) is measured along with safety; A Phase 3 study usually involves tens of thousands of people and looks at safety and efficacy in the real world.

Of importance is the demonstrated ability to prevent disease. A successful Phase 3 study is a prerequisite for vaccine approval.

Of some interest is the pace at which vaccine development has been proceeding. Normally, vaccine development is a process of several years. The current timeline of the most advanced candidates could see vaccine availability by early next year. Part of the reason for this accelerated timeline is the use of new techniques particularly mRNA vaccines. The most common method of vaccine development is to take viral or bacterial protein and inject this into the body to produce an immune response. An mRNA vaccine produces immunity in a slightly different way. mRNA is a signal for protein production in the body. When mRNA is injected into the body, it is taken into cells of the body. The patient's own protein production machinery then produces viral proteins. These proteins are then extruded from cells and produce an immune response. This greatly simplifies vaccine manufacturing as mRNA vaccine production is easier than producing a vaccine of viral proteins.

The vaccines mentioned below are currently ready to start Phase 3 studies and represent the most likely successful candidates that could shine the much-desired light at the end of the tunnel of this inglorious pandemic.

Moderna

Moderna is a United States pharmaceutical company which, surprisingly, has never taken a drug to market. It published results in the New England Journal of Medicine on July 14 describing its experience in 45 patients. An adequate immune response was generated in all patients. The company has announced plans to start a Phase 3 trial (Final trial needed for FDA approval) which will recruit 30,000 patients starting July 27. If successful, the hope is for vaccine availability in early 2021.

University of Oxford/Astra Zeneca

The University of Oxford in conjunction with Astra Zeneca have also developed an mRNA vaccine. The university has reported on its experience in 1,077 patients in a combined phase 1/2 study. The results has suggested that the vaccine does result in antibodies to the SARS-CoV-2 virus and it does not appear to be associated with significant side effects. Oxford is currently planning a Phase 3 study with patients from Brazil and South Africa and a combined Phase 2/3 study in Great Britain. If successful it hopes to have doses for emergency use in October of this year. Astra Zeneca has said it will have the capacity to produce two billion doses by 2021.

Biontech/Pfizer

Biontech is a German biotechnology company and Pfizer is a large United States drug manufacturer. They reported on July 1 of the experience with an mRNA vaccine in 45 patients. They found good antibody response at three different doses of their vaccine. The highest dose did have minor side effects of fever and sleep disturbance. They are starting Phase 3 studies this month. Of interest, the United States Government has already contracted for 100 million doses by December of this year at a cost of US$ 1.9 billion with an option to purchase an additional 500 million doses. This does depend on successful approval. If successful, Pfizer estimates the ability to produce 1.3 billion doses by the end of 2021.

CanSino Biologics

Currently there is only one vaccine worldwide that has approval (limited) in China. This has been produced by a Chinese biologic company CanSino Biologics. Unlike the previous three mentioned, this company's vaccine depends upon an adenovirus vector. The company reported its Phase 2 trial results in the Lancet on July 20. It had studied two doses in 603 patients. Both doses appeared effective in eliciting an immune response. The higher dose had a nine per cent incidence of severe side effects compared to one per cent in the lower dose. Apparently, limited approval has been granted for use in the China military, there are, however, further plans for a Phase 3 study.

Conclusion

Advances are being made in the ability to treat COVID-19 disease and to find a safe and effective vaccine. What is clear, is that several vaccines are at a very advanced stage of development and it is very likely that there will be a vaccine for COVID-19 by early 2021. What is also clear, is that the availability of the vaccine will further expose the global inequity in health care as it is predicted that there would be an initial scramble for these vaccines by the richer countries that funded much of the vaccine development. It is not surprising that the US Government has already placed an initial order of 100 million doses at a cost of USD1.9 million for one of the candidate vaccines. It is likely therefore, that by early 2021, as the richer countries get protected from vaccination, the epicentre of the pandemic will shift to poorer countries without immediate access to vaccines as they are shut out from the global supply chain due to excessive demand from the richer nations. The time for poorer nations like Jamaica to begin negotiating for a slice of the pie is now. Jamaica's leadership must begin the process of negotiating and securing international partnerships and commitments that would guarantee vaccine supply to Jamaica at the earliest possible time. If we miss the opportunity to negotiate and secure vaccine commitments now, it would already be too late once the vaccines are approved. Any delays could have potential costs in lives lost.

Meanwhile, it is important for us to continue to keep ourselves safe with the simple effective measures that have worked so far.

Stay safe.

Dr Ernest Madu, MD, FACC; and Dr Paul Edwards, MD, FACC are consultant cardiologists at the Heart Institute of the Caribbean (HIC) and HIC Heart Hospital. Correspondence to emadu@caribbeanheart.com or call 876-906-2107


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