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PROFESSOR SPECIALIZING IN DISEASES ON THE RISE OF COVID-19 VARIANT VIRUSES
By Joseph Giambrone, Auburn University professor emeritus

COVID-19 infection and hospitalization rates are falling nationwide, but experts talk in dire terms about what will happen if variants of the virus are allowed to continue to surge this spring. There is a continual threat of emerging coronavirus variants that may increase the transmissibly, increase the disease-causing ability of the virus and/or weaken the effectiveness of immunizations.

The difficulty in controlling coronaviruses has to do with how the virus replicates. As a single-stranded RNA virus, it has limited "proofreading abilities," causing mutations that over time result in genetic drift and the emergence of new variant strains. When it makes a mistake, it's not good at going back and fixing it. Those changes may give the next generation a fitness advantage, allowing it to replicate faster and cause more serious disease even in the face of vaccination.

Vaccination plays an important role in keeping birds protected, but the vast genetic diversity of the virus means that not all vaccines are cross-protective. There are hundreds and hundreds of viruses circulating and only a handful of vaccines that are able to use against them. If we don't have homologous vaccines available, we have to start looking at other vaccine types that may have more cross protection against circulating field viruses.

The spike protein of the virus, which gives it a corona shape, is divided into two unique sections. The S1 protein contains the receptor binding domain (RBD), which attaches to the ACE2 receptor of the host's cell, whereas the S2 protein allows fusion of the virus to the host cell. Significant changes in either one can cause important functional changes. Scientists believe that natural mutational changes in the S1 protein of the original coronavirus, which was endemic in horseshoe bats, exposed a new S1 spike protein.

This new protein mutated in two separate events. The first allowed the virus to infect small mammals either in the wild or in live animal markets; and later mutations, which probably occurred in live animal markets, allowed the virus to infect humans starting the pandemic sometime in late 2019 in Asia.

Many thousands of pinpoint mutations have arisen in the genome of SARS-CoV-2 virus since it emerged in late 2019, however only a few have caused a functional change in the virus. Three variants (United Kingdom, Brazil and South Africa) have undergone genetic changes in the RBD of the S1 protein. These new variants have resulted in increased transmissibility (Ro value) 50 times greater than that of the original SARS virus.

All three variants have been found in the U.S. and have doubled their frequency of occurrence every 18 days. The U.K. variant B1.1.7 has resulted in 2,300 cases in the U.S. so far. Both the U.K. and South African variant have been reported to cause more severe disease, resulting in increased pneumonia, and the need for ventilator usage. In addition, the South African variant has been shown to reduce the efficacy of the commercially available vaccines.

No doubt, variants will continue to arise, which can cause greater transmission, increased disease and reduced vaccine efficacy. Some mutant viruses will eventually replace the original SARS-CoV-2 virus because they have an improved "genetic fit," which increases virus survival.

The National Institutes of Health has stated the U.S. could see another spike in cases and hospitalizations from these variants in midspring, thereby reversing the recent downturn of positive cases and hospitalizations. This demonstrates the necessity for rapid vaccination and continued mitigations to decreased viral transmissibility and concomitant mutations.

Toward the goal, the U.S. is now vaccinating more than 14 million people per week and has promised to increase that number to 3 million per week with the recent approval of the one dose Johnson and Johnson vaccine. It is possible in the near future that resuming activities, such as international travel and attending crowded events like concerts or sporting events that we took for granted in 2019, will be contingent on proof of vaccination.

The broader issue in relation to suppressing COVID variants is the need to vaccinate as many of the world's population as can be accomplished. The longer that populations are susceptible, the faster the spread of COVID-19 and the greater the probability that variants will emerge. Dense populations in urban areas in India, China, Brazil, South Africa and Nigeria represent an extreme risk of encountering variants, some of which may be refractory to immunity stimulated by existing vaccines. Vaccination is ultimately the only practical method of suppressing COVID-19 on a worldwide basis.

Policies previously implemented by many nations involving travel bans from specific countries are an exercise in futility. The fact that a U.K. variant appeared and was widely disseminated in the U.S. within a short time of being identified illustrates the futility of imposing rigid travel restrictions. Although some island nations such as New Zealand have achieved success in closing borders, the introduction of variant strains of SARS-Cov-2 will be inevitable in most all nations, given the extent of international travel.

In addition, attempting to restrict vaccines to a specific nation or nations is regarded as both morally indefensible and ultimately self-destructive. Until the world achieves acceptable herd immunity through vaccination, no nation is safe.

The U.S. was behind in detecting variants. The problem was not a shortage of technology or expertise. Rather, scientists say, it was an absence of national leadership and coordination, plus a lack of funding and supplies for overburdened laboratories trying to juggle diagnostic testing with the hunt for genetic changes. However, as detection abilities have been ramped up, many new variants have been detected across the U.S., including notable ones in California and New York that have concerned the NIH.

One variant recently isolated from New York has been shown to be refractory to neutralization monoclonal antibodies, which are used as treatment in hospitals. Known variant cases quintupled from 471 to 2,300 in February, and most new infections in the U.S. are now being caused by variants either from domestic or foreign origin. The CDC has recently allocated $200 million for increasing the sequencing of the entire genome of 7,000 viral isolates per week to 25,000. Detection and characterization of variants require the isolation and sequencing of the nucleotide bases of the viral genome, which is not a trivial laboratory procedure.

Researchers have studied the ability of antibodies in the blood of recovered COVID-19 patients to block variants. Antibodies function by blocking emergence of the virus into the cells by attaching to the RFB of the virus or cleaving the S1 protein from the surface of the virus. Some analyses have indicated that the variant first detected in South Africa, 501Y.V2, is "more troubling" because of the number and position of key spike-protein mutations and the potential effects on vaccine efficacy.

Several vaccine producers have begun developing updated versions of their vaccines to thwart the new strains. A late-stage study conducted in the U.K. and South Africa on an experimental vaccine from Novavax appeared to support that decision, with interim results indicating the vaccine shot offered significantly more protection against the U.K. variant than the South African one.

The U.K. government has now allowed vaccine companies to undertake trials in 25 young volunteers between the ages of 18 to 30, who have been previously vaccinated with the AstraZeneca product, to be experimentally infected with a live virulent variant virus to determine their immunity. In many countries, including the U.S., such human trials would be not allowed; rather, infection studies would be done using vaccinated laboratory animals or by determining the neutralizing capability of antibodies from vaccinated humans against various variants viruses in laboratory studies.

Coronavirus will no doubt become endemic and continue to mutate, requiring the future development of new vaccines. Commercial vaccines can be developed to provide more protection against new neutralizing escape variants to be used as a booster rather quickly compared to conventual produced ones. However, they will need to be approved by the federal government, production ramped up and then administered in the arms of people. Estimates to navigate this time frame can range to six months. In addition, treatments with antibodies in the plasma of COVID-recovering patients and synthetic-laboratory-produced monoclonal antibodies using the initial SARs-Co-V2 may be less effective against these new variants.

Sarah Gilbert, a professor of vaccinology at the University of Oxford who conducted the initial research on the AstraZeneca vaccine, said, "Efforts are underway to develop a new generation of vaccines that will allow protection to be redirected to emerging variants as booster doses." The new shots could be ready for the fall, she told the BBC. Pfizer and its German partner BioNTech, as well as Moderna, and Johnson and Johnson have said their own results indicate their vaccines should still protect against severe disease, hospitalizations and death caused by the variant strain detected in South Africa.

Recent anecdotal evidence from Pfizer and Moderna indicated that these two mRNA viruses can reduce the Ro (transmission rate) values of the original SARs virus by 70%, but they have yet to indicate what effect they will have on the Ro value of the new variants.

Nevertheless, Moderna has developed and is undergoing trials with a third-shot booster containing mRNA from the South African variant. Dr. Kizzmekia Corbett, who led the team responsible for Moderna's vaccine, has referred to mRNA vaccines as a "plug and play" approach. It's possible to replace one sequence of mRNA in the vaccine for another in a matter of weeks. This allows drug companies to jump into action, creating and testing vaccines that mimic new coronavirus variants that arise. Whereas, Pfizer's chief executive officer has said that a third booster with their original mRNA vaccine should provide increased immunity against any new variant.

This supposition is called by virologist as "Original Antigenic Sin," meaning that the higher antibody levels produced against an original virus, the more resistance that can be provided against variants in the same virus family. However, continual boosting with the Johnson and Johnson and AstraZeneca recombinant vaccines, which contain an adenovirus as a carrier, may cause antibodies against the adenovirus, which could neutralize this adenovirus career virus before the body can be exposed to the internal SARs mRNA. Novavax, whose vaccine is made up of spike proteins, said it started working on new versions of its vaccine targeting the emerging strains in January and expects to select ideal candidates for either a booster or combination shot. Such alterations aren't unheard of-it happens annually with seasonal flu, which evolves more quickly than the coronaviruses.

The Coalition for Epidemic Preparedness Innovations, or CEPI, announced in January up to $140 million in funding for additional clinical research to optimize and extend the use of existing vaccines. This could include "mix-and-match" studies of different variant viral vaccine shots used in combinations that may improve the quality and strength of the immune response. Such studies could be useful in optimizing the use of available inoculations, including the AstraZeneca shot, according to the World Health Organization.

Modeling by the Institute for Health Metrics and Evaluation in Seattle predicts that, in a worst-case scenario in the U.S., widespread transmission of the South African variant and pre-pandemic levels of mobility among the vaccinated could result in about 654,000 COVID-19 deaths by May 1. Without transmission of that variant, the forecast drops to 595,000 deaths. It predicts only 38% of Americans will be vaccinated by May 1 and that herd immunity is unlikely to be a factor in slowing transmission in the coming months, even with vaccination campaigns ramping up.

With the emergence of variants and waning of immunity, it is inevitable that COVID will persist in our society, requiring annual or biannual booster vaccination, much as we have accepted annual influenza "shots." This will be a small price to pay for restoring our way of life and protecting the most vulnerable in our society.

Higher levels of specific immunity produced by annual immunizations with new variant vaccine strains and continued stringent mitigations-including double-masking and nationwide masking on all public transportation and in large, public gatherings, as well as social distancing and avoiding large crowds-are needed for the foreseeable future for slowing the evolution of variants. In the time when variants are arising, the relaxation of mitigations as is currently being done in several U.S. states will undoubtedly lead to another wave of the pandemic with increased infections, hospitalizations and deaths.

About Joseph Giambrone:

Joseph Giambrone is a professor emeritus in Auburn University's Department of Poultry Science with a joint appointment in the Department of Pathobiology in the College of Veterinary Medicine. During his graduate research career at the University of Delaware, he was part of a research group that developed the first vaccine against an antigenic variant of an avian coronavirus. During a sabbatical leave during his tenure at Auburn, he was part of a research group in Australia that sequenced the entire genome of antigenic variant of a coronavirus of chickens.

During his 42-year research career as a molecular virologist, immunologist and epidemiologist, he has made critical advancements in understanding the ecology of viral pathogens, led efforts to improve detection and surveillance of viral diseases and developed new and effective vaccines and vaccine strategies to protect commercially reared chickens as well as pathogens, such as avian influenza viruses, which have spilled over into human populations. His research has had a profound impact on practices used today to reduce the incidence and severity of viral diseases of commercially reared poultry as well in human populations.


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