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Tuesday, Dec. 1, 2020

Update on SARS-COV-2 Vaccines

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Companies hard at work to treat coronavirus

Coronaviruses are a family of large RNA viruses that infect mammals and birds and cause respiratory infections and disease. There are seven known human coronaviruses that originally appear to have come from animals. Of these seven human coronaviruses, four are largely benign and cause 25-30% of the common cold cases. The remaining three human coronaviruses are more deadly and include SARS-CoV (Severe Acute Respiratory Syndrome- Coronavirus; caused the SARS outbreak in 2002-2004), MERS-CoV (Middle East Respiratory Syndrome-related Coronavirus, an ongoing infection largely limited to the Middle East), and SARS-CoV-2 (Severe Acute Respiratory Syndrome- Coronavirus-2, the current pandemic virus that causes COVID-19 or Coronavirus Disease - 2019).

As of mid-November, the current coronavirus pandemic resulted in more than 10 million infections and more than 240,000 deaths in the U.S. alone. With cases spiking in the U.S. and Europe and winter approaching, it has been suggested that much of the world is in for a rough winter.

Based on these warnings, most people are wondering, “How do we get out of this pandemic and return to a normal life.” The end goal that has received significant attention is the development of an effective vaccine. Vaccines allow society to safely reach herd immunity that would otherwise be difficult under natural conditions. To date, no dangerous pathogen have via natural infection resulted in herd immunity.

For example, the eradication of Smallpox in 1976 was only possible with concerted worldwide vaccination efforts. The same idea holds true for the current polio eradication efforts. Through the use of an effective vaccine, the World Health Organization has limited endemic wild type polio to only two countries as of November 2020.

There are currently more than 150 SARS- CoV-2 vaccines in clinical trials around the world, with nearly 10 in phase III trials. In the U.S., there are at least four vaccines in phase III trials, with results on the efficacy of these trials expected in November or December of 2020. The four main vaccines in phase III trials in the U.S. are vaccines from Moderna, Pfizer/BioNTech, Oxford/ AstraZeneca, and Johnson & Johnson. These different vaccines represent distinct approaches, with the Moderna and Pfizer/ BioNTech vaccines being mRNA-based vaccines and the Oxford/AstraZeneca and Johnson & Johnson vaccines being adenoviral-vector-based vaccines. The mRNA-based vaccines have been around for more than 20 years but have come into their own in the last decade. The mRNA vaccines represent a new tool in the vaccine arsenal as they can be created quickly (once a viral genomic sequence is known, for example) and tested quickly. These mRNAbased vaccines rely on the power of the vaccinated host to translate the mRNA into a protein of interest.

For Moderna and Pfizer, their vaccines are focused on the spike protein. All coronaviruses have a spike protein because this is the protein responsible for viral attachment to the infected cell.

Nevertheless, regions on a coronavirus’ spike protein are unique to each virus that can be specifically targeted by the immune response to control infection with that virus. The mRNA-based vaccines are very amenable to rapid production and can be quickly constructed; however, once marketed, to remain stable, they must be stored frozen. It appears that this vaccine route requires two separate shots a few weeks apart.

The University of Oxford collaboration with AstraZeneca has taken a different approach and uses a non-replicating chimpanzee adenoviral vector that they have experience using in other studies. The vector expresses the SARS-CoV-2 spike protein and, thus, acts as an immunogen. In initial trials, a second dose increased immunity.

Johnson & Johnson uses an adenoviral vector that expresses the spike protein that they hope only requires a single shot. They are using a modified human adenoviral vector that they utilized during their creation of an Ebola vaccine. Other approaches, such as the use of inactivated whole virus, are also being used in other vaccine candidates.

It is expected that these vaccines will stimulate a robust humoral and cell-mediated immune response that would provide protection from disease caused by SAR- CoV-2 infection and possibly mitigate some level of infection. Because all available data suggests that infected humans generate an immune response to a coronavirus infection, there is no inherent reason that a vaccine should not provide protection.

Arguments have been made as to what type of immunity may be generated. In general, the types of vaccines generate an IgG antibody response and, thus, should protect the lower respiratory tract. Because IgA is often required to protect the upper respiratory tract, it remains unclear if the vaccines will prevent disease through disruption of infection of the lower respiratory tract or if they will mitigate and/ or block infection in general.

To exit the current pandemic, this is likely unimportant for the vaccinated hosts but could play a role in the length of time of the pandemic if a large percentage of folks do not get vaccinated. Also not discussed in most press releases is the ability to generate cell-mediated or T cell immunity. T cell-mediated immunity does develop in coronavirus-infected individuals and plays a vital role in host defense. Most studies seem to focus on the antibody response and then the waning of the antibody response.

These are all normal processes, and because an effective immune response to most pathogens generates immunological memory that lasts from months to years and even for a lifetime for many pathogens, these vaccines should be able to provide, should they prove to efficacious, strong protection for the vaccinated host.

On Nov. 9, a Pfizer press release suggested that their vaccine was 90% effective in blocking or preventing disease in their trial participants. This release only discussed the outcome in a small number of participants, but it did show the potential of the current crop of SARS-CoV-2 vaccines in current trials.

On Nov. 15, an independent data and safety monitoring board (DSMB) overseeing the Phase 3 trial of the investigational COVID-19 vaccine known as mRNA-1273, reviewed trial data and shared its interim analysis with the trial oversight group on the Moderna vaccine. Interim review of the data suggests that the vaccine is safe and effective at preventing symptomatic COVID-19 in adults. The DSMB reported that this vaccine candidate is safe and welltolerated and noted a vaccine efficacy rate of 94.5%.

Through the use modern techniques and accelerated trials, the hope is to develop a safe and effective SARS-CoV-2 vaccine in 12-18 months. The previous fastest vaccine to market was four years, and many take 10- 15 years to develop, test and bring to market. Certainly, the current pandemic has spurred rapid action to develop a vaccine quickly.

At present, the safety profiles look good, and there is no evidence that any safety corners are being cut. Our fingers are crossed that one of the current Phase III vaccines or current Phase I/Phase II vaccines will come to fruition and allow large-scale vaccination and us to return to our new normal lives. Lessons learned from the pandemic should spur greater surveillance techniques and new vaccine development technologies to produce future vaccines for new pathogens quickly.

Andrew D. Yurochko, Ph.D., professor and Carroll Feist Endowed Chair in viral oncology, vice chairman, Department of Microbiology and Immunology, director of research, Feist-Weiller Cancer Center

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