Approval of COVID-19 vaccines only the ‘end of the beginning’

Approval of the two mRNA COVID-19 vaccines by the FDA in mid-December and possibly two more in February does not necessarily represent the beginning of the end. To quote Winston Churchill at the time of the successful conclusion of the Battle of Britain in 1941, having the two vaccines available for administration by the end of 2020 is certainly “the end of the beginning.” In an insightful opinion article in the Dec. 4 edition of The Wall Street Journal, Dr. Tom Frieden, previously a director of the Centers for Disease Control and Prevention, noted the logistic and epidemiologic restraints relating to vaccination in the presence of escalating incidence rates in most states, and elevated hospitalizations and mortality.

It is axiomatic that unless the U.S. can effectively control COVID-19 in both rural and urban areas of the nation, restoration of the economy will not be possible. The second reality is that vaccines, under the best of circumstances, will not have any appreciable effect on the progress of COVID-19 infection in the U.S. until mid-2021. Although these vaccines provide 95% protection against clinical disease, it has not yet been determined if these vaccines protect against infection or viral transmission or the durability of the immunity. In addition, the continual presence of unstable coronaviruses in wild animals makes development of herd immunity a more difficult task. Also unknown is the amount of the population needed to be immunized to develop herd immunity. It can only be estimated based on the level of transmission. Current estimates range from 60 to 75% of the population.

The development of successful mRNA vaccines against coronaviruses in one year is not surprising because mRNA vaccines have been under development against influenza viruses for 10 years and recombinant vaccines against coronaviruses for 15 years. The finances needed to bring these vaccines to human trials never materialized, because the SARS and MERS pandemics were short lived and because the production of influenza vaccines in embryonated chicken eggs continues to be inexpensive and very efficient. What is amazing is the high level of protection afforded by these new coronavirus vaccines. No doubt the large amount of capital infused under Operation Warp Speed has greatly accelerated to their development.

Challenges facing deployment of the first vaccines developed under the Warp Speed Program include the following:

The U.S. is transitioning to a new administration. It is unclear what plan the current administration had developed for distribution of vaccines other than shifting the responsibility to states, although it is evident that significant coordination by the federal government will be essential to success. As the current Coronavirus Task Force dissolves by attrition and time, it has become increasingly irrelevant despite the vice president chairing a meeting of the body on Dec. 7. The incoming Biden administration will be faced with modifying whatever plan exists and will have to supplement logistics and resources. This presumes open and complete cooperation between the outgoing and incoming administrations—a process that appears in question.

Initial volumes of vaccine production may not achieve anticipated levels of demand for priority groups. As of the end of 2020, only 4 million Americas had been vaccinated, 27 million less than the government’s earlier estimates. It is hoped that technical problems restricting availability will be resolved to facilitate extensive administering in accordance with the predetermined list of recipients.

The requirements for a cold chain for distribution of the Pfizer vaccine should not be underrated. Although it appears that the Pfizer vaccine can be stored in ultra-low temperature freezers and transported using dry ice, reconstitution and administration at points of vaccination will be problematic. We obviously have resources to ship containers of vaccine on dry ice by air and by truck from point of manufacture to distribution depots. Problems will occur with the proverbial “last mile,” especially in rural areas. Government estimates for the end of the year for the Pfizer and Moderna vaccines were that 20 million people would receive a vaccine. However, only 4 million did. Presently there is a dearth of sufficiently trained individuals or structural space to reach the government’s expectation. It is hoped that the infrastructure for the administration for the Pfizer and Moderna vaccines will eventually reach the 20 million mark per week. Pfizer has said that a five-dose vaccine vial can contain seven doses, and Moderna is examining the efficacy of administration of a half-dose of vaccine to each person.

Administration and monitoring of COVID vaccines will present challenges. It is obvious that precise records must be kept on each recipient to schedule and confirm subsequent administration of the second booster dose. It will be critical to be able to identify any serious adverse reactions although without a coding scheme to maintain confidentiality maintaining a uniform Federal database will be impossible.

Adverse clinical events whether related or unrelated to vaccination are inevitable. Although both the Pfizer and Moderna vaccines did not result in problems during the Phase III trials, extensive vaccination involving millions of recipients will be sure to reveal clinical cases unconnected to vaccination but requiring investigation. Administration to hospital workers and the elderly in the U.K. elicited individual sensitivity to the Pfizer vaccine within two days of limited distribution. The 450 cases of Guillain-Barre Syndrome among 40 million “swine flu” vaccinations in 1972 illustrates the potential problems assorted with mass vaccination. It is contemplated that over 280 million residents in the U.S. will each receive two mRNA vaccines, assuming that young children will not be vaccinated during 2012.

It will be necessary to monitor mild reactions to the vaccines, especially after the second dose as reported from trials. Efficacy will have to be determined by evaluating the incidence of COVID-19 among vaccinates. Although antibody levels will denote response to the vaccine, protection will have to be determined concurrently with immunity to determine the correlation data. Both vaccines have shown remarkable protection. It must be determined that the vaccines can prevent viral transmission. Initial data form the Moderna vaccine indicates that it can prevent infection.

RNA viruses like coronaviruses are genetically unstable. As a consequence, RNA viruses replicate as complex and dynamic mutant swarms, called viral quasispecies. These quasispecies increase their fitness for survival by increasing their transmissibility or by escaping the host’s immune system. Recently health officials in the U.K. said they have identified at least 1,000 people who have become infected with a new strain of the coronavirus. So far, eight single mutations have occurred within the spike protein. Their scientists have said the mutation has made the virus 50 to 70 times more infectious and has been detected in other countries, including the U.S. These mutations could potentially impact the severity of the disease as well as the efficacy of the newly developed vaccines, although they have not found any evidence that they can cause vaccine failures. They caution that they must do more research before reaching any definitive conclusions about that new strain.

It is not surprising that this SARS coronavirus has undergone significant mutations in the spike protein gene. The virus has been circulating in the human population for at least one year. This virus is a single stranded RNA virus, which is genetically unstable, and mutations can occur in any of the viral genes. However, it will take a specific mutation in the area of spike protein that induces the immune response to render vaccines less effective. Therefore, continual surveillance and isolation of coronaviruses in wild and domestic animals, live animal markets and human populations need to be done and their genes sequenced to determine any important mutations of the spike protein gene. Under pressure from continual vaccination, it is likely that viral escape mutants will occur as has occurred in domestic animals over many decades. Therefore, new vaccines may need to be developed to protect against these mutant viruses. The development of a universal vaccine against the conserved region of the coronavirus spike protein could provide protection against current and new antigenic variants. However, development of a universal vaccine has been ongoing against influenza variants for the past 20 years with little beneficial results.

Acceptance of the vaccine will be critical to attaining a level of immunity that restricts transmission and persistence of the infection. There is a segment of our population characterized as “antivaxxers” who are bereft of scientific knowledge and susceptible to mischievous misinformation from the internet. This cohort will not participate in a voluntary vaccination campaign. There is a strong undercurrent of suspicion directed toward the vaccine since COVID-19 was injudiciously politicized from the first quarter of 2020 and onward. Obviously, a countrywide mandatory vaccination program will be unacceptable, however, businesses have the authority to do so. Public health authorities at the federal, state and local levels will be required to exercise transparency and to emphasize the positive health aspects and the public necessity of general acceptance of vaccination. Indifference to vaccination is especially evident in some minority communities most impacted by COVID-19. It is hoped that the success of the initial vaccines administered to health care workers, the healthy elderly and those with predisposing conditions will generate confidence in the vaccines. In the face of escalating cases and mortality, coupled with the desire to return to “a new normal,” those who are disinclined to accept the vaccine should become more confident of the safety and efficacy of the two FDA-approved products in addition to other vaccines that have yet to be tested and assigned Emergency Use status. Within two days of the release of the Pfizer vaccine, a Kaiser-Permanente study indicated a 70% willingness to be vaccinated. The concern is the substantial resistance among some minority communities and political demographics that will detract from the level of population immunity desired.

The U.S. will hopefully implement a successful vaccination program that will effectively suppress transmission of SARS-CoV-2 virus reducing incidence rates. The U.S. is not an island and it will be necessary to stimulate a broad level of immunity in all nations. Within an undetermined period, protection of those vaccinated will wane, and with restoration of international travel, critical to the World economy, the virus responsible for COVID-19 will circulate among susceptible populations and be reintroduced to the U.S. There is concern that effective vaccines will not be available to developing nations in quantities sufficient to maintain a level of immunity consistent with effective control. Also, based on the current production and administration of the vaccine, it is expected that by mid-2022 only one-fourth of the world’s population will have been vaccinated.

The World Health Organization is cooperating with organizations such as Covax to make available vaccines at minimal cost to nations with large populations and limited resources. Adenovirus-vectored vaccines, such as the AstraZeneca, Johnson and Johnson and the Russian Sputnik 5 products, appear to be effective and have the advantage of not requiring a low-temperature cold chain. They can be produced at a much faster rate at reduced cost than synthetic mRNA vaccines. These products including the vaccines from China represent opportunities to immunize a high proportion of the world’s population, especially in Africa, Latin America and Asia, with production already scheduled for Brazil and India.

Despite the promise of at least two effective vaccines, it is obvious that administration to the general population of the U.S. will not be a reality until the late spring or early summer of 2021. It is again emphasized that vaccination is not a panacea but is a component of an integrated program of prevention. Vaccination and immunization are not synonymous. Vaccination is the administration of a vaccine, and immunization is the development of immunity after vaccination. Immunity from vaccination will only be achieved two weeks after the initial dose. In the interim it will be necessary to continue with commonsense precautions. These include masking in public, avoiding gatherings, rapid antigen testing with quarantine and heightened personal hygiene. Wearing PPE in factories, packing plants and agricultural operations where manual labor is required is a necessity to maintain the health of food workers. Our optimism over a vaccine must be tempered by the reality that the U.S. has experienced 15 million confirmed cases and 300,000 fatalities, both sad statistics that are probably underestimating of the reality. We are experiencing over 200,000 incident cases and deaths daily, non-availability of ICU wards in some states and over 100,000 hospitalized. Reliable models predict up to 600,000 fatalities by the end of winter, which is before extensive immunization of our population can be achieved. Our best strategy is, therefore, to comply with public health recommendations and to hope for an expeditious distribution and administration of effective vaccines.

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.