The unprecedented scale of scientific effort being applied to countering the pandemic is already beginning to bear fruit. Current estimates of the infection fatality rate (IFR) have been lowered to a range of 0.5% to 1.0%; clinical trials showing promise for a low-cost, widely available steroid to reduce mortality could cut that by a third. “Flattening the curve” from plotting the number of deaths (y-axis) vs time (x-axis) is key to not overwhelming healthcare resources and thereby causing more casualties. However, the area under the curve that represents the total number of deaths over time is not impacted by flattening tactics such as physical distancing, masks, lockdowns, testing, or contact tracking. Given enough time, this coronavirus will spread to the uninfected. In addition to more effective treatments, the key to reducing the lethal area under the curve is not preventing exposure, but rather preventing infection after exposure. Vaccines are the likeliest solution. Status and description of vaccines currently in clinical trials is presented.

Unprecedented Scale of Scientific Effort to Halt the Pandemic

As of mid-June 2020, there are 140 COVID-19 vaccines in development worldwide. Of these, 13 are already being administered to human subjects with the remainder still at the preclinical stage. The level of effort applied to development of a COVID-19 vaccine, like the pandemic itself, is unprecedented. Indeed, the degree of scientific focus on all aspects of understanding the SARS-CoV-2 virus and the disease it causes is beyond remarkable. We should all remain optimistic that this massive application of technological resources will result in treatments, vaccines, and even cures being developed, given enough time.

Latest Estimates of Infection Fatality Rate (IFR)

But currently we have no vaccines, not even partially effective ones such as exist for influenza viruses, and there is a pool of billions of non-resistant humans across the globe for the SARS-CoV-2 virus to infect. Current estimates for COVID-19’s infection fatality rate​ (​IFR​; the number of deaths​ divided by the number of actual infections) across all age cohorts and including all comorbidities converge on a range from 0.5% to 1.0%, depending on the location of the population studied. If so, that is good news, as that range is many times lower than early estimates of the IFR. The concern is the unknown numbers of asymptomatic infections impacting the denominator that are common to all locations. But even if the IFR is half the current estimated range, i.e., 0.25% to 0.5%, this translates to approximately 2​ ,000,000 to 4,000,000 eventual premature deaths due to COVID-19 infection. The​ world is only about one-tenth the way to the high end of that estimate. Should the IFR estimates of 0.5% to 1.0% hold, then we may be only about 5% of the way to an even grimmer total​ .​

The Area Under the Curve

The mantra of health authorities is “flatten the curve” and with good reason. The y-axis of that curve is the number of deaths at any single time point, and the x-axis is time. A steep peak in the curve could well correlate with healthcare resources being overwhelmed, a situation that actually increases the number of deaths due to suboptimal care for those with serious symptoms. But flattening the curve does not affect the area under the curve – this area represents the total number of COVID-19-related deaths. Only two things can reduce the area under the curve: 1.) more effective treatments for infected persons experiencing serious symptoms, and 2.) preventative measures that can block infection even when a person has been exposed to the virus.

Will This New Coronavirus Be Persistent? (Leaky Herd Immunity)

Recent welcome news of the ability of the familiar, widely available, and inexpensive steroid drug dexamethasone to reduce mortality by one-third in COVID-19 patients on ventilators and by one-fifth​ for those on oxygen, is in the first category. But given enough time without a vaccine, the virus would inexorably work its way through the global population until there were so many previously infected (and presumably resistant) survivors that its progress would slow to a crawl. This is the concept of herd immunity. Given that the four other coronaviruses adapted to infect humans are together responsible for ~20% of common colds, some epidemiologists think that this could be a somewhat leaky herd immunity, lasting perhaps a year or two in individuals as with other coronaviruses. If that is​ the case, an effective vaccine might need to be administered annually or biannually.

Vaccines in Development

A list of 13 vaccines that are already in clinical trials is presented here; over 100 more are at the pre-clinical stage, some poised to begin human trials within a month. These 13 represent a diversity of strategies for provoking an immune response, some tried and true, and some that have never been approved for prevention of an infection. Vaccines work by predisposing our memory T cells through these surrogate viral components to attack the actual virus when we are exposed.

• genetic vaccines – use one or more of SARS-CoV-2’s own genes
• viral vector vaccines – use a virus to deliver SARS-CoV-2 genes into cells
• protein-based vaccines – use whole protein or a protein fragment from SARS-CoV-2
• whole-virus vaccines – use an unactivated version of SARS-CoV-2
• repurposed vaccines – already in use for other diseases but could also protect against COVID-19 infection

We all hope that one of these vaccines will pass regulatory muster sometime in the next 12 months, maybe even in this calendar year. It could happen. In some cases, Phase I and Phase II studies and even Phase II and Phase III are being combined for expediency. Yet it is key to keep in mind that even our initial “best candidate” that is first to receive regulatory approval after demonstrating sufficient efficacy and safety may not be the best choice two years from now. The eventual safest and most effective vaccine may not even be on the current list of preclinical candidates.

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Funding for Development and Manufacturing of a Vaccine

Another consideration is the ability to manufacture a winning vaccine at massive, unprecedented scale to extinguish this global pandemic. Although the comments column in the table below highlights several candidates claiming to be able to produce 100 million or more doses per year, a successful vaccine would need to be produced at a scale >50 times higher than that to vaccinate the world’s population.

Vaccine development not only occurs on a scale of years, but it is an expensive process and typically requires multiple candidates for ultimate success. Operation Warp Speed (OWS), a collaboration of US government departments and the biopharma private sector has been created with the aim of accelerating development of multiple COVID-19 vaccines, largely by the application of billions of dollars of federal funding to selected projects. This funding would include large-scale manufacturing of vaccines that may never receive regulatory approval, but this toss of the dice is judged to be worth the risk. OWS involvement is noted in the list below. Vaccines are presented in order of their progress in clinical trials.              

Review of Clinical Trials

Phase 1: Investigates the safety, tolerability and pharmacology of a new compound (absorption,​ tissue distribution and elimination of the drug) and usually involves 20-100 subjects.  This is the stage where small, safe doses of the compound, determined by animal toxicology studies, are gradually increased.

Phase 2: Investigates the optimal effective dose using the method of delivery or route of​ administration, dosing schedule or interval and duration of application and to continue monitoring the product safety involving 100-300 patients who are suffering from the disease.

Phase 3: Monitors further safety, effectiveness and absolute best dosage in 1,000-3,000 patients or​ more.

COVID-19 VACCINES IN CURRENTLY IN CLINICAL TRIALS