Humanity is experiencing its first exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or COVID-19 pandemic. To date, more than 20 million persons have been infected with nearly 750,000 deaths since 2019. With just a few weeks before 2021 begins, the world waits for the "cure"-not only a cure for COVID-19 but also for the social distancing, economic tumult, and the slow meltdown of healthcare system as material and human resources are exhausted. Slowly the truth is emerging; life will not return "as it was" until a safe, effective, and widely available vaccine is accepted and taken.1
Over the past 2 decades, [beta]-coronaviruses from bats have caused 3 zoonotic outbreaks, namely, SARS-CoV (2002-2003), MERS-CoV (2012), and SARS-CoV-2 beginning in 2019, and there will probably be similar outbreaks in the future.2 The first case of SARS was identified in Foshan, China, in November 2002. By July 2003, 8096 cases were found in 30 countries with 774 deaths worldwide before the outbreak was declared "over." In 2012, MERS-CoV was identified in a patient who died of respiratory failure in Saudi Arabia. Cases continued to emerge in 27 other countries, with a 35% mortality rate and significant morbidity. From 2012 to January 2020, there were 2506 laboratory-confirmed MERS-CoV cases reported to the World Health Organization, with 863 deaths and 1 known virus transmission from camel to human. In December 2019, pneumonia caused by SARS-CoV-2 was reported in Wuhan, China, with rapid transmission and atypical symptoms during the early phase of the infection. It is likely that this outbreak began months before the official announcement.3
VACCINE DEVELOPMENT OBSTACLES
First, neither immune responses to COVID-19 are completely understood, nor which vaccine platform is the most effective. Even with rising numbers of infections across the world, induced immunity appears to vary significantly, which suggests herd immunity may be more difficult to achieve than first believed. Immune responses to infection differ widely, from no symptoms to mild and severe expressions. Still unknown is why older persons are more susceptible to infection and why asymptomatic persons shed virus longer than persons with symptoms and experience lower levels of antibody-mediated immunity.1
COVID-19 infection begins in the respiratory tract through interactions with angiotensin-converting enzyme 2 receptor sites. This is the foundation for some of the life-threatening inflammatory response in severe COVID-19. Science has learned quickly that failure to achieve early control of COVID-19 in the lungs resulted in greater viral loads and risk for lethal inflammatory immunopathology with adult respiratory distress syndrome. Finally, the deadliest aspect of COVID-19 infection is the capacity SARS-CoV-2 to mask the immune response, hiding the long and asymptomatic incubation period of 2 to 12 days compared with the 1- to 4-day period for the flu.1
VACCINE PLATFORMS
Fortunately, science had a multiplicity of vaccine platforms developed over the past 20 years from advances in molecular biology and vaccinology available to develop a vaccine. This variance in platforms has increased the likelihood of developing a safe and effective vaccine during this pandemic. Furthermore, it is likely that more vaccines will have to be built from multiple platforms in the future.4 The majority of vaccine platforms use the S-protein of the SARS-CoV virus and include the follwoing2,4:
* live attenuated vaccine/live virus
* inactive virus, which is safer than live virus platform
* subunit vaccine (no live particles), based on the synthetic peptides or recombinant antigenic proteins to elicit immune responses
* viral vector vaccine with risk of integration of the viral genome into the host genome (widely with MERS-CoV with good results)
* DNA platforms that elicit both cytotoxic and humoral immunity; however, titers are low; possible risk of insertion of foreign DNA into the host genome, which may cause cell abnormalities
* RNA vaccines-translate mRNA in the cytosol of the host cell, which eliminates the risk of integration into the host genome; however, reports of excessive immune responses including fever and sore arm
In addition to vaccines, immunity can be achieved by use of sera from convalescent patients, identified as passive immunization or adoptive immunity.2
More than 160 vaccine candidates have emerged in a 6-month period, using platforms used extensively to develop treatments for cancer and infectious disease.1 The Table describes vaccines nearing the end of phase 3 trials seeking approval at the end of 2020 or early 2021.1,5-7 This list will change significantly in 2021 and beyond.
CONCERNS GOING FORWARD
COVID-19 vaccines will likely be needed for many years if SARS-CoV-2 becomes established in the population like influenza to reduce morbidity and mortality and create herd immunity. Manufacturing enough doses consistent across lots and available to all will be a difficult undertaking.4 Continuous monitoring for safety and effectiveness for each approved vaccine will also be necessary going forward.8
The mRNA vaccine platform appears to be a promising approach going forward in this pandemic. This platform empowers rapid vaccine development compared with other platforms.9 This vaccine pre-exposes the immune system to a small amount of encoded proteins usually generated by the pathogen and degrades over time, which reduces the risk of continuous stimulation of the immune system.2 Some suggest the world should also prepare for a future with multiple partially protective SARS-CoV-2 vaccines that confer partial immunity and weaken over time.8
It has been proposed to implement human "challenge" trials or exposure to COVID after vaccination.10 This is a crucial part of vaccine development described as a challenge test, to assess the level of protection afforded by the vaccine and safety. Usually, this is part of preclinical evaluation and uses an animal model and was used to develop vaccines for malaria, typhoid, and cholera. However, this challenge test was applied for malaria, typhoid, and cholera, there were established treatments for these diseases, and subjects experiencing disease could receive care. A challenge test for COVID-19 in humans is ethically problematic because there is no standard treatment for COVID-19 at this time. While challenge testing could be accomplished by using an attenuated virus such as an artificial mutant, the results may not be generalizable if the attenuated virus is not similar enough to the circulating strain.10,11
Another difficult aspect of challenge testing is the availability of adequate healthcare for subjects in the case of adverse events. Challenge testing if approved must take place in settings that ensure access to all necessary levels of care.10,11 Consider that at least 10 countries in Africa lack access to ventilators and even more lack critical care beds. These areas should be excluded from this type of research.10
FINAL OBSERVATIONS
2020 has been a remarkable year with the worldwide mobilization of resources and dedication of vaccine researchers across the globe.8 Many expect breakthrough "cure" for COVID-19, to do something soon, despite the fact that understanding this virus has just begun. The desire for quick solutions is a dangerous attitude that can negatively affect judgments regarding approvals. All trials must be transparent to reduce false information in order to build trust and reduce vaccine hesitancy.11
Nearly 166 vaccines are in preclinical and clinical development.1 A pan-coronavirus vaccine is what is ultimately needed. This should be a universal priority based on international funding to support the development, manufacturing, and stockpiling of the coronavirus vaccines.2 Also needed going forward may be a different vaccine strategy to protect seniors and the young whose participation has been limited in clinical trials.1
For current updates, discussion, and education, check out COVID-19 Conversations at https://covid19conversations.org/ by the American Public Health Association and the National Academy of Medicine.
References