Introduction

Vaccines are the most effective tools for the prophylaxis of infectious diseases. Attenuated pathogens were used for vaccination initially to cope with diseases such as smallpox, anthrax, tuberculosis, and pasteurellosis. Later, at the end of the 19th century, the inactivation of microorganisms to use them for vaccination was invented, and many vaccines were produced using this technique against various diseases. Technological improvements especially in molecular genetics facilitated the development of innovative vaccines such as recombinant hepatitis B vaccine or more recently the messenger RNA (mRNA) vaccines [1, 2].

The development process is different for varying types of vaccines. Therefore, launching a new vaccine, including preclinical studies, clinical trials, approval procedures, and mass production takes 5 years to 10 years generally. The number of preclinical studies conducted for the development of vaccines is high. However, many of them fail in the clinical phases. The rate for getting approval from administrative institutions such as the Food and Drug Administration (FDA) or European Medicines Agency (EMA) is less than 10% [3]. Therefore, certain steps are followed during the development of a vaccine from the research phase to the post-market period. A vaccine candidate should pass the following steps to come onto the market [4–6]:

• (1)

  Exploratory phase: In this stage, components of the vaccine formulation are studied. For subunit vaccines, antigenic proteins are determined or epitope peptides can be identified using in silico methods. The adjuvant to be used in the vaccine formulation is selected. For live vaccines, the pathogen is attenuated. For killed vaccines, the inactivation methodology of the pathogen is optimized. The vaccine candidate is formulated to be tested in the preclinical phase.

• (2)

  Preclinical phase: The aim of this stage is to have an idea about the safety and efficacy of vaccine candidate using cell cultures and experimental animals. The disease in humans is mimicked in an appropriate animal model. Single and repeated-dose toxicity, pharmacokinetics, pharmacodynamics, immunogenicity, and local tolerance of the vaccine candidate are tested. If the animal model is not appropriate for the disease type, preclinical results would not reflect the situation in humans.

• (3)

  Clinical phase: In this stage, the candidate vaccine is tested in healthy human volunteers. Safety, immunogenicity, and clinical efficacy profiles are evaluated in three distinct phases for approval, and one more stage (phase 4) is included for post-market surveillance.

  • Phase 1: The safety of the vaccine candidate is evaluated in a small number of healthy humans ranging from 20 to 100. Different doses of vaccine are administered to volunteers to find out any possible side effects, and finally, an optimal dosage for the vaccine is determined. This stage takes several months, and approximately 70% of the candidates move to phase 2.

  • Phase 2: The safety and immunogenicity of the vaccine are evaluated by randomized controlled studies in a higher number of humans ranging from 100 to 1,000. The immune responses are compared between the volunteers who received the vaccine and placebo controls. Sometimes efficacy data might be obtained in this phase. This stage takes several months to 2 years, and approximately 33% of the candidates move to phase 3.

  • Phase 3: The safety and clinical efficacy of the vaccine are tested in this final phase in a large population of volunteers (several thousand). Most of the safety data including long-term or rare side effects are provided in this phase. This stage takes 1 year to 4 years. If the vaccine provides successful safety and efficacy data in phase 3, the manufacturer applies for a biologics license application to administrative institutions such as FDA or EMA to get approval for marketing. Approximately 25–30% of the vaccines move to phase 4.

  • Phase 4: The vaccines with approval after phase 3 come onto the market. However, potential safety and efficacy issues of the vaccine are still monitored during the post-market period, which is called phase 4.

The conventional vaccine development paradigm spreads over a wide period of time, which is not appropriate for emergency situations such as pandemics. Therefore, a new paradigm for the “emergency” vaccines has been applied to develop coronavirus disease 2019 (COVID-19) vaccines in a shorter time. Although shortening the process created hesitancy about the safety and efficacy of vaccines in some people, the majority of the world population was fully vaccinated with COVID-19 vaccines. The aim of this article is to discuss the vaccine development paradigm during emergency situations, the effect of COVID-19 on this process, and the hesitancy against vaccines developed using a new paradigm.

Vaccine development in the era of epidemics and pandemics

Over the past two decades, many epidemics including influenza, Ebola, Zika, measles, and recently the COVID-19 pandemic threatened human health seriously. New outbreaks urge us to be prepared for combating new or reemerging diseases. Since vaccines have a pivotal role in this combat, preparedness for vaccine development is crucial in the era of epidemics and pandemics [7].

In the spring of 2009, a novel influenza A (H1N1) virus pandemic strain pdm09 emerged, which was composed of an unusual repertoire of influenza genes different than the ones identified previously. Therefore, the cross-protection provided by seasonal influenza vaccines against A(H1N1)pdm09 was little [8, 9]. However, cross-neutralization was demonstrated using sera from mice immunized with DNA vaccines encoding hemagglutinin (HA) proteins of A/California/04/2009 or A/South Carolina/1/1918 [10]. Following the identification of 2009 H1N1, companies from the vaccine industry cooperated with public health and regulatory agencies for the development of a vaccine against A(H1N1)pdm09. In mid-September 2009, FDA approved four monovalent A(H1N1)pdm09 vaccines including inactivated ones produced by CSL Biotherapies, Novartis, and Sanofi Pasteur as well as a live attenuated vaccine produced by MedImmune [11, 12]. It was estimated that the vaccination from October 2009 to April 2010 in the United States (US) prevented up to 1.5 million clinical cases and 500 deaths [8]. Development of A(H1N1)pdm09 vaccines was relatively rapid because the technology and key regulators needed for influenza vaccines were well-established [7].

The rapidness of influenza vaccine development was not valid for the works on Ebola, Zika, and severe acute respiratory syndrome (SARS). In November 2002, an outbreak of SARS coronavirus (SARS-CoV) started and rapidly spread worldwide. The disease resulted in a relatively small number of deaths. However, the mortality and transmissibility rates of the virus were high. Therefore, work on the vaccine development against SARS-CoV was started immediately but the epidemic ended approximately 8 months later. Eventually, the funds were cut, and the development of the SARS-CoV vaccine was interrupted. Only two candidates, a DNA vaccine and an inactivated vaccine, were evaluated in the phase 1 trial [13].

In December 2013, the Ebola epidemic started when a 1.5-year-old boy from a village in Guinea was supposed to be infected by bats, and soon five more cases of fatal diarrhea were reported in the same area. A disease alert was issued officially in January 2014 in the district and the disease spread to Conakry, the capital city of Guinea. Next, a medical alert was issued by Guinea’s Ministry of Health for an unidentified disease in March 2014. The illness was identified by the Pasteur Institute (France) as Ebola virus disease (EVD) caused by Zaire ebolavirus, and the World Health Organization (WHO) declared an EVD outbreak officially on March 23, 2014 [14]. The epidemic continued for more than 24 months with widespread transmission in Guinea, Liberia, and Sierra Leone. There was sufficient time for vaccine development, and WHO impelled acceleration for it. Although Ebola vaccines had been developed and tested in non-human primates previously, these candidates were not evaluated in clinical trials during the epidemic [13]. Merck was funded by the US government for the development of an Ebola vaccine but the vaccine could not be produced before the epidemic ended. The company did not stop the work, and the vaccine (Ervebo) was approved by the EMA and FDA at the end of 2019, 70 months after the epidemic started. In 2018, Ervebo was used as an investigational vaccine against the world’s second largest EVD outbreak occurred in the Democratic Republic of the Congo [7, 15, 16].

How were the COVID-19 vaccines developed so quickly?

The typical vaccine development timeline is useless in public health emergencies such as COVID-19. A protective vaccine was needed in a short time to get over the devastating effects of the pandemic. A vaccine was also needed quickly because of the high mutation rate of the virus. If the vaccine is developed too late, its efficacy could be limited against new variants [28]. The process of vaccine development has many stages from research to marketing. Therefore, various local and international organizations such as government agencies, academia, and pharmaceutical companies should cooperate to accelerate the process [29]. Rapid information sharing through this cooperation can enable diversification, risk sharing, and the efficient use of resources by preventing unnecessary repetitions [30].

As an example of this cooperation, a program known as Operation Warp Speed (OWS) was announced in the US on May 15, 2020. Within the scope of OWS, the Department of Defense (DOD) and the Department of Health and Human Services (HHS) cooperated with private companies for the development of COVID-19 vaccines, therapeutics, and diagnostics to control the pandemic [31]. More than 13 billion US dollars (USD) were committed for the COVID-19 vaccines through OWS. Roughly 2.5 billion USD of this budget was allocated for vaccine research and development, and the rest for purchase agreements. Other high-income countries such as the UK and the EU were also allocated high budgets for COVID-19 vaccines [30].

Technological preparedness also accelerated COVID-19 vaccine development. The high speed for the RNA-based vaccines was not surprising because this platform has been used for the development of vaccines against various diseases such as cancer for more than 30 years, and some of them entered clinical trials. Although previous RNA-based vaccine candidates have not been granted approval for use in humans until COVID-19, this technology showed its success against SARS-CoV-2 [1]. The process for the development of mRNA vaccines against COVID-19 is depicted in Figure 1.

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Figure 1. 

Development of mRNA vaccines against COVID-19. mRNA molecules encoding spike protein of SARS-CoV-2 are formulated with lipid nanoparticles, and injected intramuscularly. Immune cells in the body receive the mRNA molecules, and the spike protein is produced by these immune cells followed by the production of antibodies specific to spike protein. If the vaccinated person is infected with SARS-CoV-2, the virus is neutralized by the specific antibodies

Improvements in omics sciences, bioinformatics, and synthetic biology also sped up the development of COVID-19 vaccines. Determination of potential antigens and epitopes, the interaction between virus and human cells, schedules for vaccination, and issues related to vaccine safety and efficacy are laborious and costly taking too much time in conventional vaccinology. However, in silico prediction methods following computational and mathematical approaches help for the elimination of vaccine candidates showing low potential for safety and efficacy [25].

Conclusion

Vaccines are critical countermeasures in public health emergencies such as pandemics. Like other medical products for use in human health, the development of vaccines requires critical steps in preclinical and clinical studies, which takes at least five years. However, this duration is too long at the time of the pandemic, and an efficient vaccine is highly desired in a shorter time than the traditional process. Therefore, an atypical process can be followed in pandemics, such as shortening the duration of clinical phases normally taking a long time in vaccine development. Approval of the vaccines for pandemics is also different than normal times, considered in the context of EUA. COVID-19 had devastating effects with high rates of mortality and morbidity worldwide. Therefore, the development of vaccines was supported, and EUA was granted to some vaccines in less than a year. These vaccines restricted the speed of the COVID-19 pandemic lowering the number of deaths. However, the shortened time for vaccine development and EUA increased vaccine hesitancy, especially among people with low education, low income, high religiosity, and at a young age.