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COVID-19: Lessons From Failure And Success

December 2019, a turning point in everyone's life: Millions of individuals become infected as the COVID-19 pandemic abruptly strikes the whole world. The coronavirus pandemic has flipped our world on its head, changing the way we think and behave in every aspect of our lives. Plans for social gatherings, academic activities, work, and relationships with the people we care about needed to be revised. Zoom meetings, social isolation, masks, PCR testing, quarantines, and lockdowns became commonplace. When the pandemic started, mankind believed that once the vaccine was available, the pandemic would be under control and the threat of COVID-19 would eventually fade away. The losses from the global COVID-19 pandemic amount to a staggering economic toll in the trillions of dollars, in addition to the significant losses in life, health and well-being (Hlávka & Rose, 2023). However, crises are catalysts for change, and need is the primary driver of innovation. The COVID-19 pandemic has prompted an unprecedented mobilization of resources to discover SARS-CoV-2 vaccines and treatment options. The debut of COVID-19 two years ago catapulted mRNA-based technologies into the center of public attention (Fang et al., 2022). The knowledge gained through the use of mRNA technology to combat COVID-19 is helpful in developing therapies and vaccines to cure existing infections and may help avert future pandemics.


Vaccination: A Boot Camp For The Immune System

The development of a powerful vaccine to halt the unprecedented spread of COVID-19 confronted the scientific community and the pharmaceutical sector with an overwhelming task. Astonishingly, just a year after the COVID-19 pandemic, a vaccine was engineered, produced, tested, authorized, and deployed internationally, sparing numerous lives. (Kalinke et al., 2022). However, despite the delivery of billions of vaccine doses in large global vaccination campaigns, the long-term protection against COVID-19 infection that had been hoped for was far from being achieved. While vaccination has helped tremendously in preventing hospitalizations, serious illnesses and deaths related to COVID-19, even after repeated boosters or doses, vaccinated people could still get sick and spread the disease to others (Haas et al., 2022; Wu et al., 2023). Vaccines instruct the body to protect itself from infection without exposing it to full infection. They work by simulating the presence of a pathogen in the body and activating the body's natural defenses. All vaccinations contain an antigen (also known as an immunogen), which is any substance that triggers an immune response. Until recently, vaccines against viruses contained one of three types of antigens: inactivated or dead viruses, live, weakened viruses that cannot cause disease, or viral protein fragments such as the spike proteins on the surface of SARS-CoV-2 viruses - the causative agent of COVID-19 - which mediate attachment to the target cell, thus enabling infection (How Do Vaccines Work?, 2020).

Figure 1 - The COVID-19 vaccine: a winding but lightning-fast road (Mukherjee, 2020).

In response to the viral antigens in the vaccine, B cells, a subset of immune cells, produce antibodies that are unique to the virus. Antibodies are proteins that recognize and bind to viruses, preventing them from attaching to a receptor molecule on the target cell, thereby neutralizing them. B cells are produced in the bone marrow but are widely dispersed throughout the body, ready to grow and attack pathogens or foreign substances. After an infection has been cleared, B cells cease growing and their numbers decline until only a few remain for continued surveillance or monitoring. This population of long-lived cells is called memory B cells (Alberts et al., 2003). Should we encounter the same virus in the future, the memory B cells will quickly activate to massively produce virus-specific antibodies. Antibodies bind to the invasive viruses to stop infection and shield us from disease. The immune system thus acquires the necessary training to fight and prevent infection by being exposed to the vaccine's harmless viral antigens. From this moment on, a person is considered immunized (Alberts et al., 2003; Nicholson, 2016).


COVID-19 Vaccine: The mRNA Revolution

The shining beacon during the COVID-19 pandemic has been the lightning-fast development of effective vaccines that work by harnessing the power of messenger RNA, or mRNA. Proteins are required for almost all biological processes. While DNA contains all the information cells need to produce proteins, mRNA actually produces those proteins. Assuming that conventional vaccines carry viral hardware, i.e. the actual viral proteins, one can think of messenger RNA vaccines as carrying the viral software that instructs cells how to produce the spike protein (Weissman, 2022). All COVID-19 vaccines approved by the FDA to date use the spike protein, which is specific to the SARS-CoV-2 virus. Vaccine mRNA is taken up by muscle and immune cells when administered intramuscularly, transferred to local lymph nodes and concentrated in the spleen (Castruita et al., 2023). Although the injected mRNA is rapidly degraded after injection, it directs the cells to produce more spike proteins, which subsequently stimulate the B cells to produce antibodies. These antibodies fight the virus if the immunized person is later exposed to it (Servick, 2020). Concerns about mRNA vaccines revolve around two main issues: first, whether or not mRNA is dangerous; Second, how effective mRNA vaccines are compared to traditional vaccines.

Figure 2 - mRNA COVID-19 vaccines instruct cells how to make the S protein found on the surface of the SARS-CoV-2 virus. (Bokat-Lindell, 2021).

Uncertainty has been expressed about the possibility that mRNA vaccines could alter the recipient's DNA. However, such a notion is scientifically unfounded, as (vaccine) mRNA does not reach the cell nucleus, where our DNA resides. In addition, RNA is rapidly degraded a few days after injection, which is why multiple vaccinations are required to achieve optimal immune response and protection (Haas et al., 2022). In terms of safety, some research has shown that mRNA-based COVID-19 vaccines are associated with a higher risk of serious adverse events such as coagulation disorders and acute cardiac events, as well as a higher likelihood of thromboembolic and thrombocytopenic events. An increased but rare risk of associated myocarditis and pericarditis has also been associated with vaccination, particularly in males aged 12 to 39 years. Increasing the time between the first and second dose can further reduce this risk. However, the US Food and Drug Administration (FDA) has given its seal of approval to both mRNA vaccines, Pfizer and Moderna, and the Center for Disease Control and Prevention (CDC) has deemed them safe and very effective at avoiding severe or fatal cases of COVID-19 (Maragakis & Kelen, 2022).


When it comes to effectiveness, people usually assume that a good vaccine will protect against disease for years. While the mRNA-based COVID-19 vaccines stimulate the production of antibodies that inactivate the SARS-CoV-2 virus and protect us from serious illness, these antibodies start to wear off a few months after vaccination (Accordino et al., 2023). As a result, infections are still prevalent in vaccinated recipients, who may become infected more than once. However, this does not necessarily mean that the vaccine is not effective. In fact, immunization against COVID-19 has unquestionably offered widespread protection against disease and is closely linked to the prevention of serious diseases. This is evidenced by a 10.5-fold higher hospitalization rate in unvaccinated individuals compared to fully vaccinated individuals (Havers et al., 2022; Tenforde et al., 2021). Additionally, even an actual bout of COVID-19 does not provide lasting protection, as people naturally contract the disease multiple times. This shows that recurrent SARS-CoV-2 infections are not due to an insufficient effect of vaccination, but rather due to fundamental and unique properties of the coronaviruses themselves.

Figure 3 - Hospitalizations due to COVID-19 are 10.5 times higher among unvaccinated than vaccinated individuals (Brody, 2021).

Coronaviruses of Animals: Was the Writing on The Wall?

The COVID-19 pandemic has emphasized the threat that zoonotic diseases, or diseases carried from animals to humans, pose to humanity. Indeed, 75% of new human disorders discovered in the previous three decades fell into the aforementioned category (Salyer et al., 2017). This highlights the need of a one-health approach to disease management: human health is inextricably linked to animal health and the environment in which we live (Francis, 2017). With this in mind, it is vital that humans take all lessons from the coronaviruses that are currently infecting animals, particularly those for which effective veterinary vaccinations are already available. Numerous animal coronaviruses infect domestic pets such as dogs and cats, as well as potential coronavirus reservoirs such as bats, pangolins, rodents, and livestock such as cattle, pigs, and poultry (Sariol & Perlman, 2020). These viruses can cause a variety of ailments, the majority of which manifest as gastroenteritis or respiratory problems. Indeed, a number of veterinary vaccines have been developed to protect cattle and domestic animals from coronavirus, and they all appear to operate in the same way: they protect animals from severe, life-threatening disease, but not from the virus itself. Such immunity is often short-lived, requires frequent boosting and does not prevent re-infection (Saif, 2004). Also animals can contract an infection, recover from it, and contract it again. This is akin to what happens to humans. Perhaps there have been red flags since the beginning, and the writing was on the wall all along. Unlike viruses such as measles, polio, and smallpox, for which immunizations are effective and long-lasting, coronaviruses simply fall short of meeting the expectations of how vaccines should operate. Each of the several viral families has its own distinctive biological characteristics. Some viruses appear to engage the immune system in a way that inhibits long-term re-infection, whether by natural infection or vaccination, whereas others do not. For instance, massive vaccination campaigns were successful in eliminating smallpox, but in striking contrast, there are some viruses for which immunization is utterly ineffective, such as HIV, the virus that causes AIDS (Cohen, 2020; Pollard & Bijker, 2021).


The failure to develop an effective HIV vaccine that can instruct the human immune system to destroy the HIV virus prompted scientists to investigate alternative methods of infection prevention. With tens of millions of people infected with HIV at risk of becoming ill and dying, researchers turned their attention to developing antiviral therapies that slow HIV replication (M. S. Cohen et al., 2011; Kemnic; & Gulick, 2023). And then failure turned into ultimate success. The same applies to COVID-19 disease management. So far, three antiviral drugs have been approved for use against COVID-19, and all target highly conserved regions of SARS-CoV-2 virus that rarely change through mutation. The three COVID-19 antivirals approved by the FDA, Molnupiravir, Paxlovid, and Remdesivir, target replication, the core functionality of the SARS-CoV-2 viruses. The ultimate goal of antiviral drugs is to ensure that the viruses infecting each person are the last of their kind (Vangeel et al., 2022). And this is where successful treatment may become prevention: as the AIDS pandemic taught us, by preventing a virus from multiplying, one can prevent it from spreading. While antiviral therapy cannot replace vaccination, it does offer the opportunity to contain a global pandemic using tools that are unlikely to become obsolete in generations to come.

Figure 4 - COVID-19 vaccines have failed to provide long-term protective immunity to prevent breakthrough infections (Binder, 2021).

Conclusions

As aforementioned, coronaviruses do not produce effective or long-lasting immunity when infecting humans or other animals. Recovery from coronavirus infection in animals, humans, or pets does not confer lasting immunity to subsequent infections. While the coronavirus vaccine protects both humans and animals against serious, life-threatening infection, it does not provide effective, lifelong protection against reinfection. For the entire virus family, this seems to be the norm rather than the exception. The warning signs were indeed there all along; perhaps the inability of COVID-19 vaccines to provide lifelong immunity could have been foreseen. With this understanding, the community should be now better equipped to fight against future coronavirus pandemics. While the pandemic caused massive and countless deaths, it also spurred tremendous scientific advances, such as the approval and introduction of groundbreaking mRNA vaccines and the development of novel antiviral drugs that help prevent disease transmission while improving people's quality of life and reducing disease burden. However, it must be acknowledged that the biology of the coronavirus family provides extra challenges that must be overcome in order to effectively combat future pandemics.

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