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The Cutting Edge: New COVID 19 developments as fall approaches


First of all, the numbers:


Worldwide, there have been over 23 million COVID-19 cases and 803,000 deaths as of this writing (https://www.worldometers.info/coronavirus/#countries). Over 5.8 million cases and 180,000 deaths have been in the U.S. Georgia has over 250,000 COVID-19 cases and 5000 deaths—good for the fifth highest totals for any state in the union. To put that in perspective, Georgia now has had more COVID-19 cases than Germany, a country with 84 million people. And Chatham County, which was spared early in the pandemic, has made up for lost time, with over 6600 cases and over 100 deaths as of this writing.

The good news locally is that the number of COVID-19 cases and hospitalizations in Chatham County seemed to have peaked in late July, as have the percentage of positive tests (https://covid19.gachd.org/covid-19-data-and-charts/ ). The community transmission index, defined as the average number of cases over the previous 14 days, is still unacceptably high here (456 new cases/100,000 population as of August 17; low is defined as less than 10 cases per 100,000 population), and the percentage of positive cases is, as well (around 9.4%; low is less than 5%), so we have a ways to go yet, but at least things seem to be slowly getting better.


Of course, we’ve been here before. The community transmission index was only 45 as recently as June 15. We’re over ten times that high at this point. So with schools opening back up this week, I’ll temper my enthusiasm for now.


The myriad failures of our public health system in allowing the COVID-19 pandemic to get so completely out of hand have been well-documented in other blog posts here. I won’t go over them again at this point. That would be like beating a dead, or even a zombified, horse. Instead, I’m going to look at a few bits of news that might help illuminate our way out of this mess.


· New Salivary COVID-19 Testing. One of the primary failures of the COVID-19 pandemic in this country has been in the testing arena. Our test availability has substantially lagged that of the rest of the developed world, and a defective CDC test early on crippled our ability to track viral progression in the U.S. This let the virus spread, well, everywhere. If we cannot test adequately, we cannot perform the most basic epidemiologic exercise: To identify the sick and separate them from the well. Readily available, inexpensive and rapid testing could help our lives resume some sense of normalcy—but that has not been the case in the United States at any point in this pandemic.


That may be about to change.


The standard nasal swab tests used during this pandemic in the U.S. have been the so-called PCR, or polymerase chain reaction, tests, which are used to check for the presence of viral RNA. These tests are very sensitive and specific, but they have their shortcomings. They can only be read by someone with specialized processing equipment, for example. This limits their availability. They are not cheap. The number of tests which can be performed can be limited by the availability of testing equipment and reagents. PCR tests are so sensitive that they can give “positive” tests for dead viral particles long after the virus has been largely eliminated and the patient is no longer contagious.


Dr. Michael Mina, a professor of epidemiology at Harvard, has become a champion of the regular use of a simple salivary antigen test for COVID-19 (https://www.theatlantic.com/health/archive/2020/08/how-to-test-every-american-for-covid-19-every-day/615217/ ). This sort of test, which is inexpensive (the target price is $1 per test) and can be mass-produced in large quantities, can deliver a result in 15 minutes or less. The results can be read by any layperson, at home, without requiring special equipment—sort of like the home pregnancy tests we have all become familiar with. People could test before they enter any public venue. Test negative, you may enter; test positive, and you get sent home. Dr. Mina’s idea is that we test pretty much everyone, every day. And while the salivary test is not as sensitive as the viral RNA-based PCR nasal swab tests commonly used so far in the pandemic, it has the advantage of being much less expensive, much more rapid and much more capable of being mass-produced. It also does not give the late-phase false positive tests seen with the ultrasensitive PCR tests. The salivary tests are, in essence, a test of COVID-19 contagiousness.


Why are these values important? To be effective, testing has to move faster than the virus—and so far, we have not been able to do that.


Most COVID-19 patients don’t produce enough viral particles to be detectable until 2-3 days after exposure. Patients may not have symptoms for several days after that; in fact, about 40% do not have any symptoms at all. The backlog of PCR testing for COVID-19 has been so significant that it often takes a week or more (and sometimes up to 14 days) after testing is performed for results to be available. During that time, an infected person could unwittingly spread his contagion to dozens of others.


Rapid, inexpensive, ubiquitous testing, like the above-mentioned salivary test, could change all of that.


E25 Bio, a Cambridge, Massachusetts startup, has developed a salivary antigen test for the SARS CoV-2 virus’s spike protein, a distinctive protein on the outside of the viral capsid which is unique to that virus.

Here’s the kicker: This form of testing was just approved by the FDA.


SalivaDirect, a salivary antigen test developed by researchers at Yale University which is similar to the e25 Bio test, has been used successfully on a trial basis during the recent NBA season. The test costs about $10 per sample. The FDA approved it for widespread use this week (https://www.wsj.com/articles/the-fda-authorizes-a-cheap-fast-saliva-testand-the-nba-is-involved-11597508654).


This could be a game-changer.


· Vaccine development. There are lots of potential SARS CoV-2 vaccines out there. Several are in Phase III testing, which is the last phase before FDA approval. The most prominent have been the Moderna vaccine, the Pfizer vaccine and the Oxford vaccine, being marketed by Astra-Zeneca. Other vaccines in the news have been those developed by Russia (which announced that it is ready to begin administering its vaccine now) and China. All in all, there are over 250 vaccine candidates being pursued globally, with 30 in human-phase clinical trials and another 25 scheduled to enter human-phase trials in 2020 (https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/on-pins-and-needles-will-covid-19-vaccines-save-the-world#).


Given the promising early results, it seems likely that at least one, and perhaps several, COVID-19 vaccines should be available for use sometime between the fourth quarter of 2020 and the first quarter of 2021. The early approval of such a vaccine would likely be granted under the FDA’s emergency use authorization (EUA) guidelines. The rapidity of vaccine authorization would be unprecedented. The previous record for the development of a vaccine was the mumps vaccine, which took four years.


There are reasons for optimism for the development of an effective COVID-19 vaccine. Published data suggest a relatively slow mutation rate for the SARS CoV-2 virus—a rate four times slower than the rate of the virus that causes seasonal influenza. Moreover, multiple vaccine candidate so far have shown promise by causing the production of immune responses which mimic those of patients recovering from COVID-19. That’s good news.


It is clear that not all vaccines are created equal. The ideal vaccine candidate will be a single-dose vaccine which is safe and which confers durable immunity and resistance to infection in 100% of all vaccinated persons, ideally with effects lasting for years. Durable immune responses would provoke both an antibody response (humoral immunity) and a response from the so-called T-cells, which are the repositories of the immune system’s “memory” (cellular immunity). Moreover, once such a vaccine is produced, there is the challenge of manufacture and distribution. Vaccines have to be broadly administered to be truly effective in a population.


Here’s an overview of the current vaccines on the horizon:


Moderna (mRNA-1273). This is a vaccine developed by a Massachusetts company in conjunction with the U.S. National Institutes of Health (NIH) which uses snippets of the virus’s messenger RNA to create viral proteins which mimic the SARS CoV-2 virus. This allows the vaccinated person’s immune system to recognize the virus. The Moderna vaccine started Phase III clinical trials in the U.S., beginning in Savannah, on July 27, 2020. The Phase II trials were favorable, producing vigorous antibody and T-cell responses in tested subjects. Moderna hopes to have a usable vaccine by early 2021. The company has struck a deal with the Swiss manufacturer Lonza which will allow it to produce up to a billion doses of vaccine per year. If licensed, this vaccine would be the first licensed mRNA vaccine in history (https://www.wsj.com/articles/modernas-covid-19-vaccine-moves-to-bigger-study-11594760401).


Pfizer (BNT 162b2). This is another mRNA vaccine developed in conjunction with a German biotechnology company called BioNTech. They launched a combined Phase II/III trial on July 27 in the U.S., South America and Europe. Preliminary results show both antibody and T-cell responses in tested subjects. It requires two doses. Some recipients had flu-like symptoms. This vaccine has a contract with the U.S. government to provide 100 million doses by December 2020, and a possible 1.3 billion doses by the end of 2021.


University of Oxford (ChAdOx1 nCoV-19). This vaccine is being developed by Oxford University, under the direction of Oxford’s Dr. Sarah Gilbert, in conjunction with the biopharmaceutical giant Astra Zeneca. It’s a viral vector vaccine, utilizing a method in which the SARS CoV-2’s spike protein is transferred to a weakened version of a chimpanzee adenovirus, which causes the common cold. The vaccine requires two doses. The Phase I and II trials showed a strong immune response from both antibodies and T-cells, with only minor side effects such as fatigue, low-grade fever and headache. Phase III trials are now underway in the U.S., South America, Europe and South Africa. The vaccine may be available for distribution by the end of 2020. They hope to produce a billion doses by the end of 2021, which they plan to distribute at cost.


Novavax. This company’s vaccine, developed by a Maryland company, uses a pair of direct injections of the SARS CoV-2 spike protein delivered 21 days apart, with the concomitant use of an adjuvant designed to boost the immune response. The vaccine was well-tolerated in Phase I and early Phase II trials and produced an antibody response in the tested subjects. Phase III trials are slated for September. This vaccine has received funding from both the U.S, government and the Bill and Melinda Gates Foundation (https://www.wsj.com/articles/covid-19-vaccine-candidate-from-novavax-starts-midstage-trial-11597645503).


Sinovac Biotech Limited (CoronaVac). This is a vaccine by a Chinese company, partnering with a Brazilian research consortium, which uses an inactivated or “killed” vaccine similar to the influenza vaccine. Phase II trials showed that this vaccine produced antibodies to SARS CoV-2. The vaccine has entered Phase III clinical trials in Brazil.


Sinopharm. This vaccine, produced by the state-run Chinese pharmaceutical company, uses an inactivated version of the SARS CoV-2 virus and showed antibody production in tested subjects (T-cell responses were not noted). The results of the Phase II trials were published in JAMA on August 13. The vaccine was well-tolerated with only minimal side effects. Phase III trials began in mid-July in the United Arab Emirates; Peru and Bahrain are also being geared as testing sites (https://www.wsj.com/articles/china-says-it-will-have-covid-19-vaccine-ready-this-year-11595521469).


CanSino Biologics (Ad5-nCoV). This Chinese vaccine, developed in conjunction with the Bejing Institute of Biotechnology, uses an adenovirus vector in a similar method to the Oxford vaccine. However, this vaccine used a weakened human adenovirus, as opposed to a chimpanzee adenovirus, raising concerns that the response rates may be less if vaccinated persons have some prior adenovirus exposure. The vaccine showed a good antibody and T-cell immune response after a single injection, with minor side effects such as low-grade fever and injection site pain. Phase III trials are now beginning in Saudi Arabia and in Russia. The Chinese plan to start administering this vaccine to its military personnel in fall of 2020.


The Gamaleya National Center of Epidemiology and Microbiology (Sputnik V). This vaccine, developed in Russia, uses a viral vector method similar to the Oxford vaccine, with two different weakened adenovirus strains being utilized to deliver the SARS CoV-2 spike protein to the recipient. It requires two injections 21 days apart. The researchers claim strong antibody and T-cell responses although they have published no data from the two small-scale trials (38 recipients) which they have undertaken so far. Despite the lack of published information, the Russian government has already authorized this vaccine for widespread use, claiming that it was the first COVID 19 vaccine to be approved in the world (https://www.cnbc.com/2020/08/20/russia-coronavirus-vaccine-to-be-tested-on-40000-volunteers-research-institute-claims.html ). They plan to enter Phase III clinical trials in August, although the WHO lists this vaccine as only being in Phase I. The Russians plan to start full-scale production of their vaccine in September 2020.


There is a chance that either demonstration of vaccination or proof of COVID-19 immunity may be required prior to entering crowded gatherings such as concerts or sporting events, or in certain workplace environments, such as schools and hospitals (https://www.nationalgeographic.com/science/2020/08/how-coronavirus-covid-vaccine-mandate-would-actually-work-cvd/ ). Mandatory annual influenza vaccination is already required for most hospital workers, so this would not be unprecedented. It has been estimated that so-called “herd immunity” would be achieved at a rate of ~70% vaccination and/or exposure. Until that level is reached, however, other methods of clearance, such as proof of vaccination or a negative rapid saliva test for COVID-19, may be mandatory for resumption of participation in large-scale group events and even social affairs such as weddings or funerals. Given that the first vaccines will likely not be available until late 2020 or early 2021, and given that at-risk populations will likely be vaccinated first, it may be the latter part of 2021 until Americans even begin to approach the true “herd” level of immunity—and that’s assuming that everyone is willing to be vaccinated. Recent experience, of course, suggests otherwise. A study published in JAMA this past June suggested that only 30% of Americans would be willing to be immunized if a COVID-19 vaccine were available in the near-term.


Welcome to the latest version of the “new normal,” evolving even as we speak.

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