*3.2.1 Discovery (1-5 years)*

The discovery phase generally consists of learning all aspects of the microbe we are trying to combat (e.g., structure, mechanism of action, etc.) Once SARS-CoV-2 was identified as a type of coronavirus, researchers were able to sequence its genome. From here, the spike protein was selected as a unique target based on its function allowing the virus to penetrate host cells and cause infection. Additionally, the spike protein had been targeted before against the Middle East respiratory syndrome (MERS) coronavirus. This precedent allowed the discovery phase to be accelerated to weeks or months rather than years.

#### *3.2.2 Preclinical (2-4 years)*

The preclinical stage generally consists of sifting through potential antigens (such as the spike protein) and deciding which will produce the best immune response and long-lasting protection. This is determined by assessing the safety of candidates for each antigen in cell and tissue cultures as well as in live animal testing. Traditionally, studies are performed on rats and mice; however, the rise of transgenic "humanized" mice, genetically modified with human genetic components, has aided in generalization toward human bodily responses. Researchers must also determine appropriate dosing and delivery form (e.g., injection, pill, etc.). Once this has been completed, the candidate vaccine moves on to the clinical stages. And how did this notoriously tedious process happen so quickly in the case of Covid-19? One example was found in March 2020, when Janssen reported that their novel technology platform, used in its Ebola and novel RSV and HIV viral vector vaccines, was effective against Covid-19. Thus, decades of research on the platform's delivery mechanism, ideal thresholds, and animal study proof-of-concept were utilized to jumpstart the development timeline.

#### *3.2.3 Phase I clinical trial (1-2 years)*

The main goal of a Phase I trial is to show that the vaccine is safe in humans and how the body receives it. A small group of volunteers is enrolled. Careful attention

*Myths Surrounding Covid-19 Vaccine Candidates: A Guide to Fight Back DOI: http://dx.doi.org/10.5772/intechopen.98714*

is given to signs of adverse events, such as toxicity, organ damage, and death. After the trial is completed, data is analyzed and submitted to the FDA for approval to begin Phase II trials. The FDA has the ability at any point to intervene if one or more serious adverse events are found. If a treatment has already been shown to work for a different condition, the Phase I trial can be shortened or accelerated to Phase II since the vaccine has proven safe in human patients. As was the case with Covid-19, multiple manufacturers were able to combine Phase I and Phase II trials since the steps can be done in parallel without compromising oversight. The experience with the delivery system used for Ebola in Janssen's case is a key example.

#### *3.2.4 Phase II clinical trial (2 years)*

Phase II trials primarily focus on narrowing down the ideal dosage to maximize effectiveness and limit side effects. A larger patient population is used. Patients are assigned to multiple groups with varying doses, delivery methods, or controls to compare outcomes. All treatments given have been previously tested (including placebo or current vaccine standard), and this step is meant to pick a "best" scenario. When the trial concludes, the results of each group are compared to determine if the vaccine is better than current treatment/vaccine resources and, if so, ideal dosing/delivery. This is a major checkpoint whereby the FDA can either discontinue the study due to adverse events/ineffectiveness or push it through to Phase III trials.

#### *3.2.5 Phase III clinical trial (2-3 years)*

The main hallmark of a Phase III trial is its size, typically around 3,000 participants. Enrolling this many patients with a disease can be a drawn-out process depending on disease prevalence and geographical distribution, often lasting several years. Perhaps the most remarkable feat of the Covid-19 clinical trial race was the ability of vaccine studies to enroll record numbers of patients in record time. Take, for instance, the Pfizer Phase III trial, which recruited over 43,000 participants in just four months. This magnificent accomplishment was able to both shave off precious time and instill greater confidence in the public and scientific community due to the sheer sample size. After all, the number of participants was over ten times greater than that of a typical vaccine candidate. One might argue that this was an invaluable marketing strategy given the shortened development timeline. While this is likely true, it is important to realize that corners were not cut in enrolling patients either. On the contrary, pharmaceutical manufacturers worked with epidemiologists to ensure that the patient population recruited for the studies was representative of the target population for vaccine administration. In layman's terms, groups that are typically hard to reach in general studies (e.g., underserved groups, those at highest risk of transmission) were given priority in enrollment efforts. Once all trial data is compiled, a New Drug Application (NDA) is filed with the FDA, asking for consideration to bring the vaccine to market.

#### *3.2.6 FDA approval/review (1 year)*

One cannot understate the amount of administrative burden and patience that goes into reaching this point, much less achieving FDA authorization. A common question asked by patients after witnessing the Covid-19 spectacle is, "Why can't we approve everything this fast?" An excellent question, indeed, given the abundance of vaccines needed for incurable diseases. To answer this, let us talk about what goes into the FDA's decision once an NDA hits its desk. The first component a manufacturer must prove is that the vaccine is safe and effective throughout all clinical

trial data. From here, the decision moves toward logistics. Is there a manufacturing process in place? Can this process consistently meet the needs of the general public? Are the batches equivalent to clinical trial data in terms of effectiveness and safety? If all of these boxes are checked, then approval is a possibility. Several panels meet to consider the vaccine data submitted for approval and licensure/regulation grants. The reason for the year timeline is based on a variety of factors. First, a large percentage of applications are incomplete, with required studies missing. Next, a candidate is put on a priority ranking list in which drugs are reviewed based on global need. Then, the FDA must meet with sponsors to ensure no corners were cut and that transparency was insured. Finally, an in-depth manufacturing analysis must be conducted to ensure that the vaccine distribution can meet the global needs of world populations (especially underserved and at-risk groups).

As another wonder of Covid-19 vaccine development, two decisions were made that cut the necessary FDA review period down to less than three weeks: parallel review and anticipatory manufacturing. Since the Covid-19 pandemic was logically considered priority #1, all possible resources were given to evaluate and approve/reject clinical trial data upon submission. Additionally, trial transparency and adverse reaction monitoring was performed concurrently to ensure proper oversight. These cut the typical six-month to one-year delay off of the majority of pre-NDA phases. Anticipatory manufacturing, the production of unapproved vaccines in anticipation of approval, was a previously unproven idea that investing in potential candidates would be cost-effective in the long run and shave previous months or even years off the vaccine distribution timeline. Consequentially, this could save millions of lives by slowing the pandemic morbidity and mortality. This gamble has proven largely successful in the early months of vaccine rollout, and specific examples can be found under the "Introduction."

## *3.2.7 Manufacturing (6 months-3 years)*

As mentioned, anticipatory manufacturing was the key to jumpstarting the vaccine production timeline. Currently, AstraZeneca/Oxford is producing an astounding 200 million doses of their Covid-19 vaccine per month. To give perspective, during the H1N1 outbreak, AstraZeneca was able to produce only 17 million doses of their H1N1 vaccine. That represents a roughly twelve-time increase in production compared to the previous pandemic [17]. While this is not a perfect comparison given differing circumstances, it is both probable and likely that the jumpstart in production and massive funding overhauls contributed to maximizing vaccine production.

#### *3.2.8 Phase IV clinical trial (optional)*

Phase IV trials are studies of adverse serious events and safety hazards that arise once a vaccine is approved and made available on the market. The FDA carefully monitors such instances through MedWatch, a service allowing providers, patients, and the trial sponsor to report a suspicious event. At any point, additional Phase IV trials may be commissioned by the FDA or sponsor to examine vaccine effects for varying benefits, risks, and patient populations [18].

#### **3.3 Myth #3: the only way to reach herd immunity and end the pandemic is by letting the virus spread**

Herd immunity has risen to prominence in both the scientific community and the general public due to its unique role in infectious disease outbreaks. To set the

#### *Myths Surrounding Covid-19 Vaccine Candidates: A Guide to Fight Back DOI: http://dx.doi.org/10.5772/intechopen.98714*

record straight, herd immunity is the only proven method of definitively preventing the spread of infectious diseases to the point of being statistically irrelevant. This is achieved by a large percentage of the population, called the herd immunity threshold, being protected from infection (**Figure 3**). Consequently, the unprotected (e.g., uninfected individuals, individuals who cannot or choose not to get vaccinated) also become protected due to the interrupted transmission chain. This part, in most cases, is largely understood. Where the record gets bent is in HOW herd immunity is reached. It is important to understand that there are two routes by which herd immunity can be achieved: natural infection and vaccines [19].

#### *3.3.1 Natural infection*

When enough individuals in the population have recovered from a specific disease and developed lasting antibodies against future infection, herd immunity can theoretically be reached. However, the issue with this myth's underlying assumption is that relying on natural infection alone ignores two common deviants: reinfection and health toll.

While admittedly, the evidence for reinfection risk is limited given the novel nature of the pandemic, there have been clear instances of Covid-19 reinfection in the community. This phenomenon is dependent on an individual's antibody levels and appears to heighten in risk between six months to a year. Significant reinfection incidence can substantially harp a community's progression toward herd immunity due to waning antibody responses.

While a community could theoretically remove all protective measures and allow the disease to run rampant until herd immunity is achieved, this would allow the full brunt of the disease to affect the community. In layman's terms, this means that millions of individuals could suffer and potentially die unnecessarily. In July 2020, experts predicted that approximately 70% of the U.S. population would need to recover from Covid-19 infection to slow disease spread. Underlying this number was the reality that more than five million individuals could perish before this feat was achieved. As you can probably guess, such a situation is unacceptable, and hence social protective measures were mandated/strongly encouraged until vaccines could fill their role in ending the pandemic [20].

#### *3.3.2 Vaccines*

As mentioned, a strong antibody response against the target disease is key to achieving herd immunity. Vaccines remain the quickest and most efficient way of promoting antibody responses on a mass scale. Unlike natural infection, vaccinedriven immunity does not require illness to achieve protection. Herd immunity has been successfully reached against contagious diseases, including rubella, polio, smallpox, diphtheria, and many more. In the long run, vaccines offer a great way to protect newborns and immunocompromised individuals from disease without suffering from the disease itself. While vaccine-driven immunity is the gold standard in fighting back against pandemics such as the Covid-19 pandemic, it is not without faults. Several barriers remain in the fight against Covid-19 that need to be solved before the world can declare victory. First, vaccine hesitancy, as we hashed out in detail before, is a predominant risk to vaccine uptake. If individuals choose not to get vaccinated, herd immunity becomes much harder to reach. Please see "Introduction" for more details. Next is the issue of protection duration. While preliminary studies have shown adequate antibody levels for at least six months post-infection, the exact antibody level drop-off timeline is unknown. Thus, protection from vaccination may be insufficient and require a "booster" dose down

#### **Figure 3.**

*"The top box shows an outbreak in a community in which a few people are infected (shown in red) and the rest are healthy but unimmunized (shown in blue); the illness spreads freely through the population. The middle box shows a population where a small number have been immunized (shown in yellow); those not immunized become infected while those immunized do not. In the bottom box, a large proportion of the population have been immunized; this prevents the illness from spreading significantly, including to unimmunized people. In the first two examples, most healthy unimmunized people become infected, whereas in the bottom example only one fourth of the healthy unimmunized people become infected." Source: Reproduced from Tkarcher under the creative commons attribution-share alike 4.0 international license.*

the road. Additionally, new variants of the Covid-19 virus may be less efficiently targeted by the existing vaccines and require uptake of new vaccines specially made to counter such variants. Finally, outbreak control, while traditionally thought of on a community level, relies on limited transmission in surrounding regions as well. Thus, uneven vaccine distribution and resulting low transmission rates around an area can impact the ability of that area to contain the virus assuming individuals travel to and from [21].
