History Of COVID-19 Vaccine Development

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19, was unceremoniously identified in late 2019. Its genetic sequence was promptly published on 11 January 2020, a move that, in hindsight, triggered an urgent and frankly frantic international response. The world, it seemed, needed to prepare for an outbreak, and, more importantly, accelerate the development of a preventive COVID-19 vaccine. Since that rather inconvenient discovery in 2020, vaccine development has been pushed forward with an almost unsettling speed, facilitated by what was optimistically called "unprecedented collaboration" within the multinational pharmaceutical industry and among various governments.

By June 2020, an astounding tens of billions of dollars had been poured into this global endeavor. Corporations, governments, international health organizations, and even university research groups collectively invested in developing dozens of vaccine candidates. The goal, rather ambitious at the time, was to prepare for global vaccination programs to immunize against COVID‑19 infection. According to the Coalition for Epidemic Preparedness Innovations (CEPI), the geographic distribution of this frantic COVID‑19 vaccine development showed North American entities leading the charge with about 40% of the activity. Asia and Australia followed with 30%, Europe contributed 26%, and a few scattered projects could be found in South America and Africa. A truly global effort, if you ignore the glaring disparities.

In February 2020, the World Health Organization (WHO), ever the purveyor of cautious optimism, stated that it did not expect a vaccine against SARS‑CoV‑2 to become available in less than 18 months. And yet, virologist Paul Offit later remarked, with a touch of understatement, that the development of a safe and effective vaccine within a mere 11 months was nothing short of a remarkable feat. The rapidly escalating global infection rate of COVID‑19 throughout 2020 certainly provided ample motivation, spurring international alliances and government efforts to urgently marshal resources. The aim was to produce multiple vaccines on drastically shortened timelines, with four distinct vaccine candidates remarkably entering human evaluation as early as March (as detailed in COVID-19 vaccine § Clinical research).

The early birds of vaccine authorization emerged from unexpected corners. On 24 June 2020, China gave its nod to the CanSino vaccine for limited use within its military, alongside two inactivated virus vaccines designated for emergency use among high-risk occupations. A little over a month later, on 11 August 2020, Russia grandly announced the approval of its Sputnik V vaccine for emergency use. However, the initial fanfare was somewhat dampened by the reality that, a month later, only small quantities of the vaccine had actually been distributed for use outside of its ongoing phase 3 trial.

The Western world eventually caught up, or perhaps merely followed a more transparent, albeit slower, process. The Pfizer–BioNTech partnership, a name that would soon become ubiquitous, submitted an Emergency Use Authorization (EUA) request to the U.S. Food and Drug Administration (FDA) for their mRNA vaccine BNT162b2 (active ingredient tozinameran) on 20 November 2020. This was a critical step. Just shy of two weeks later, on 2 December 2020, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) granted temporary regulatory approval for the Pfizer–BioNTech vaccine. This made the UK the first country to approve this specific vaccine, and indeed, the first country in the Western world to approve the use of any COVID‑19 vaccine. By 21 December 2020, a cascade of countries and the European Union had authorized or approved the Pfizer–BioNTech COVID‑19 vaccine. Meanwhile, Bahrain and the United Arab Emirates had already granted emergency marketing authorization for the Sinopharm BIBP vaccine. The US FDA followed suit on 11 December 2020, granting an EUA for the Pfizer–BioNTech COVID‑19 vaccine. A mere week later, they extended an EUA for mRNA-1273 (active ingredient elasomeran), the Moderna vaccine, further solidifying the mRNA platform's prominence.

In a slightly more niche, yet perhaps equally telling, development, the Russian government announced on 31 March 2021 the registration of what they claimed was the world's first COVID‑19 vaccine for animals. Dubbed Carnivac-Cov, this inactivated vaccine was designed for carnivorous animals, including household pets, with the stated goal of preventing viral mutations that could arise during interspecies transmission of SARS-CoV-2. Because, naturally, our furry companions also needed protection.

More recently, in October 2022, China introduced an oral vaccine developed by CanSino Biologics, leveraging its adenovirus model. This marked another innovative, if somewhat late-stage, approach to vaccine delivery.

Despite the widespread availability of mRNA and viral vector vaccines, the uncomfortable truth remains that worldwide vaccine equity has yet to be achieved. The ongoing development and continued use of whole inactivated virus (WIV) and protein-based vaccines have been recommended, particularly for deployment in developing countries, as a pragmatic measure to help dampen further waves of the pandemic. A stark reminder that scientific breakthroughs don't inherently solve distribution problems.

Planning and investment

The journey to a COVID‑19 vaccine, as mentioned, was largely driven by an "unprecedented collaboration" between the multinational pharmaceutical industry and various governments. One might even call it a shotgun marriage born of global desperation. The Coalition for Epidemic Preparedness Innovations (CEPI) noted that the geographic distribution of this intense vaccine development effort saw North American entities capturing approximately 40% of the activity, while Asia and Australia accounted for 30%, Europe 26%, and only a smattering of projects originating from South America and Africa. This geographical imbalance, of course, would later contribute to predictable disparities in access.

Committing to the initial "first-in-human" testing of a vaccine candidate is no small undertaking; it represents a significant capital expenditure for vaccine developers. Estimates placed this cost at anywhere from US $14 million to US$ 25 million for a typical Phase I trial program, with some even reaching as high as US $70 million. To put this into perspective, during the [Ebola virus epidemic of 2013–16](/Western_African_Ebola_virus_epidemic), 37 vaccine candidates were urgently developed, yet only one ultimately became a licensed vaccine, with the total cost to confirm its efficacy in Phase II–III trials hovering around a staggering US$ 1 billion. The scale of the COVID-19 challenge dwarfed even that.

International organizations

Access to COVID‑19 Tools (ACT) Accelerator

The Access to COVID-19 Tools Accelerator (ACT Accelerator or ACT-A), also known by its more verbose title, "The Global Collaboration to Accelerate the Development, Production and Equitable Access to New COVID-19 diagnostics, therapeutics and vaccines," was a G20 initiative. It was officially announced by pro-tem Chair Mohammed al-Jadaan on 24 April 2020, with a simultaneous call to action issued by the World Health Organization (WHO). By January 2022, it had solidified its position as the largest international effort ever undertaken to achieve equitable access to COVID-19 health technologies. A noble goal, if perpetually challenging.

National governments

Governments worldwide, faced with an existential threat, opened their coffers with varying degrees of enthusiasm and strategic foresight.

Canada announced an initial CA $275 million in funding, distributed across 96 vaccine research projects at Canadian companies and universities. The plan also ambitiously included the establishment of a "vaccine bank," a strategic reserve to be deployed should another coronavirus outbreak dare to rear its head. A further investment of CA$ 1.1 billion was later added, specifically designated to support clinical trials and develop the crucial manufacturing and supply chains required for vaccine distribution. On 4 May, the Canadian government further pledged CA $850 million to the WHO's live streaming fundraising effort, which aimed to raise US$ 8 billion for COVID‑19 vaccines and preparedness. A respectable contribution, for a country that probably didn't want to be in this position in the first place.

China, ever the pragmatist, provided low-rate loans to a chosen vaccine developer through its central bank and, with remarkable efficiency, "quickly made land available for the company" to construct expansive production plants. As of June 2020, a significant six of the eleven COVID‑19 vaccine candidates in early-stage human testing were being developed by Chinese organizations. The government provided substantial support to three Chinese vaccine companies and research institutes, financing research, facilitating clinical trials, and prioritizing the rapid manufacturing of the most promising candidates. Their focus, it seemed, was on swift evidence of efficacy, perhaps with a slightly less vocal emphasis on safety in the initial stages. On 18 May, China committed US $2 billion to support the WHO's broader efforts against [COVID‑19](/COVID-19). Later, on 22 July, China announced a US$ 1 billion loan to ensure its vaccine would be accessible to nations in Latin America and the Caribbean. This was followed by Chinese Premier Li Keqiang's announcement on 24 August that Cambodia, Laos, Myanmar, Thailand, and Vietnam would receive priority access to the vaccine once it became widely available. A clear demonstration of vaccine diplomacy in action.

US Government Accountability Office diagram comparing a traditional vaccine development timeline to a safe, possible expedited method timeline.

Great Britain, not to be outdone, formed a COVID‑19 vaccine task force in April 2020. This initiative was designed to galvanize local efforts for accelerated vaccine development through collaborations spanning industry, universities, and government agencies. It was an ambitious, all-encompassing endeavor, covering every phase from initial research to large-scale manufacturing. The vaccine development projects at the University of Oxford and Imperial College of London alone received a substantial £44 million in financing.

In the United States, the Biomedical Advanced Research and Development Authority (BARDA), a federal agency dedicated to funding disease-fighting technology, announced investments approaching US $1 billion. These funds were earmarked to support American [COVID‑19](/COVID-19) vaccine development and the manufacture of the most promising candidates. On 16 April, BARDA made a significant US$ 483 million investment in vaccine developer Moderna and its partner, Johnson & Johnson. BARDA further allocated an additional US$4 billion for development, playing a pivotal role in other programs aimed at developing six to eight vaccine candidates destined for clinical study well into 2021 by companies such as Sanofi Pasteur and Regeneron. On 15 May, the US government unveiled a fast-track program, somewhat dramatically named Operation Warp Speed. Its mandate was to push multiple vaccine candidates into clinical trials by the autumn of 2020 and, even more ambitiously, to manufacture 300 million doses of a licensed vaccine by January 2021. The project's chief advisor was Moncef Slaoui, with General Gustave Perna serving as its chief operating officer. In June, the Warp Speed team declared its intention to collaborate with seven companies developing vaccine candidates: Moderna, Johnson & Johnson, Merck, Pfizer, the University of Oxford in partnership with AstraZeneca, and two others. Curiously, Pfizer later clarified that "all the investment for R&D was made by Pfizer at risk," suggesting a more complex relationship than initial government announcements might have implied.

Pharmaceutical companies

The colossal scale of the pandemic necessitated the involvement of large pharmaceutical companies, those with the existing infrastructure and expertise to produce vaccines at an industrial scale. Giants like Johnson & Johnson, AstraZeneca, and GlaxoSmithKline (GSK) quickly formed intricate alliances with specialized biotechnology companies, governments, and academic institutions. This intricate web of partnerships was designed to accelerate the progression towards an effective vaccine. To combine financial muscle with manufacturing prowess, particularly for a pandemic requiring adjuvanted vaccine technology, GSK even joined forces with Sanofi in an unusual partnership between multinational companies to support accelerated vaccine development. Such collaborations, while seemingly altruistic, rarely are.

By June 2020, the collective investment from corporations, governments, international health organizations, and university research groups had indeed reached tens of billions of dollars, all funneled into developing dozens of vaccine candidates and laying the groundwork for global vaccination programs. However, this corporate investment, driven by the inherent need to generate value for public shareholders, inevitably raised concerns. Critics worried about a "market-based approach" to vaccine development, the potential for exorbitant pricing of eventual licensed vaccines, and the likelihood of preferred access for distribution to affluent countries first, leaving densely populated, impoverished nations—where the pandemic might rage most aggressively—with sparse or no distribution, simply because they couldn't afford it. The collaboration between the University of Oxford and AstraZeneca, a global pharmaceutical company based in the UK, exemplified these concerns, sparking questions about pricing and the equitable sharing of future profits from international vaccine sales, especially given the public funding received by the British government and the university. AstraZeneca, perhaps preemptively, stated that its initial vaccine pricing would not include a profit margin for the company while the pandemic remained an expanding global threat. A temporary reprieve, at best.

In June, AstraZeneca solidified a US$750 million deal with CEPI and Gavi, the Vaccine Alliance, enabling them to manufacture and distribute 300 million doses if its Oxford vaccine candidate proved to be both safe and effective. This agreement reportedly boosted the company's total production capacity to over 2 billion doses per year. Commercializing pandemic vaccines is inherently a high-risk business venture, carrying the potential for billions of dollars in losses from development and pre-market manufacturing costs if candidate vaccines fail to meet safety and efficacy standards. Pfizer, notably, expressed disinterest in a government partnership, perceiving it as an unnecessary "third party" that would only impede progress. Furthermore, there were persistent concerns that rapid-development programs—such as Operation Warp Speed—were prioritizing vaccine candidates primarily for their manufacturing advantages rather than for optimal safety and efficacy profiles. A necessary compromise, or a dangerous shortcut? Only time would tell.

Development

CEPI, in its rather clinical classification, categorized vaccine development stages as "exploratory" (involving the initial planning and design of a candidate without any in vivo evaluation), "preclinical" (encompassing in vivo evaluation and preparation for manufacturing a compound suitable for human testing), or the more advanced initiation of Phase I safety studies in healthy people. As of September, a total of 321 vaccine candidates were reported to be in active development, either as confirmed projects undergoing clinical trials or in earlier "exploratory" or "preclinical" stages. A staggering number, reflecting the sheer scale of the global effort.

Early development

After the initial isolation of the elusive coronavirus in December 2019, its genetic sequence was made public on 11 January 2020. This pivotal moment triggered an urgent, and frankly, somewhat panicked international scramble to brace for an inevitable outbreak and to expedite the development of a preventive vaccine.

In February 2020, the WHO, ever the voice of tempered expectations, cautioned that a vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, was unlikely to materialize in under 18 months. Yet, the relentless and rapidly accelerating global infection rate of COVID‑19 throughout 2020 forced the hand of international alliances and governments. Resources were urgently marshaled to produce multiple vaccines on drastically compressed timelines, resulting in four vaccine candidates entering human evaluation as early as March (as detailed in the table of clinical trials initiated in 2020, further below).

By April 2020, the landscape was teeming with activity, with "almost 80 companies and institutes in 19 countries" engaged in what could only be described as a virtual gold rush. In the same month, CEPI estimated that approximately six COVID‑19 vaccine candidates should be selected by international coalitions for progression through Phase II–III trials. Of these, three would need to be rigorously streamlined through regulatory and quality assurance processes for eventual licensing, at an estimated total cost of at least US$2 billion. Another analysis, perhaps with a touch more realism, suggested that ten candidates would require simultaneous initial development before a select few could be chosen for the final, arduous path to licensure.

Cyber-espionage efforts

In a predictable, yet still disheartening, turn of events, the global race for a vaccine became a ripe target for illicit activities. In July 2020, a joint statement was issued by the UK's National Cyber Security Centre, the Canadian Communications Security Establishment, and the U.S.'s Homeland Security Department Cybersecurity and Infrastructure Security Agency, along with the National Security Agency (NSA). Their collective assertion was that Russian state-backed hackers, specifically the notorious group known as Cozy Bear (APT29), were actively attempting to pilfer COVID‑19 treatment and vaccine research from academic and pharmaceutical institutions across various countries. Russia, predictably, denied the claim, despite its well-documented history of cyber-espionage and cyberattacks against foreign targets.

In November 2020, Microsoft further reported that another Russian state-sponsored hacking group, Fancy Bear (APT28), alongside North Korean state-sponsored hacking groups nicknamed "Zinc" and "Cerium," had been implicated in recent cyberattacks. These attacks targeted researchers diligently working on COVID-19 vaccines in countries including Canada, France, India, South Korea, and the U.S., as well as the World Health Organization itself. The cyberattackers employed both crude brute force and sophisticated phishing techniques to compromise computer systems. Microsoft's report indicated that at least nine healthcare institutions were targeted, and some of these attempts regrettably proved successful. In February 2021, South Korea's National Intelligence Service provided a closed-door briefing to members of the South Korean parliament, detailing North Korean efforts to steal COVID-19 vaccine technology from Pfizer. It seems even a global pandemic couldn't deter the baser instincts of international espionage.

Preclinical research

NIAID (NIH) scientist researching COVID‑19 vaccine examines agar plate. (30 January 2020)

In April 2020, the WHO, in a rare display of unified purpose, issued a public statement. This declaration, endorsed by dozens of vaccine scientists worldwide, pledged a concerted collaboration to accelerate the development of a vaccine against COVID‑19. The WHO coalition actively encouraged international cooperation among organizations developing vaccine candidates, national regulatory and policy agencies, financial contributors, public health associations, and governments. The ultimate goal, a rather ambitious one, was to facilitate the eventual manufacturing of a successful vaccine in quantities sufficient to supply all affected regions, with a particular emphasis on low-resource countries that would undoubtedly be left behind otherwise.

A sober analysis of past vaccine development efforts reveals a rather grim reality: failure rates typically range from 84% to 90%. Given that COVID‑19 presented a novel viral target—its properties still largely unknown and requiring innovative vaccine technologies and development strategies—the inherent risks associated with developing a successful vaccine across all stages of preclinical and clinical research were exceptionally high. It was, in essence, a shot in the dark, with billions of lives hanging in the balance.

To assess the potential for vaccine efficacy, unprecedented computer simulations were rapidly deployed, and new COVID‑19-specific animal models were developed through multinational efforts. Of the confirmed active vaccine candidates, approximately 70% were being developed by private companies, with the remaining projects under the purview of academic institutions, government coalitions, and various health organizations. Historically, the probability of an infectious disease vaccine candidate successfully navigating preclinical barriers and reaching Phase I of human testing stands at a modest 41–57%. The odds, it seemed, were not exactly in humanity's favor.

Challenges

The breakneck speed of development and the sheer urgency of producing a vaccine for the COVID‑19 pandemic, while necessary, inevitably heightened the risks and the potential for failure in delivering a safe and effective vaccine. One study, examining the period between 2006 and 2015, found that the success rate of obtaining approval from Phase I to successful Phase III trials for vaccines was a mere 16.2%. CEPI's own projections indicated an even more bleak potential success rate of only 10% for vaccine candidates in development during 2020. These were not encouraging statistics.

Adding to the complexity, research at universities was significantly hampered by the very mitigation strategies implemented to combat the virus, namely physical distancing protocols and the widespread closure of laboratories. The irony was not lost on those attempting to solve the problem while simultaneously being constrained by it.

Biosafety

Early research, aimed at assessing vaccine efficacy using COVID‑19-specific animal models—such as ACE2-transgenic mice, other laboratory animals, and non-human primates—highlighted a critical need for biosafety-level 3 containment measures. These stringent precautions were essential for handling live viruses and necessitated robust international coordination to ensure standardized safety procedures across all research facilities. Cutting corners was not an option when dealing with a novel pathogen.

Antibody-dependent enhancement

Although the primary objective of a potential vaccine is to elicit a robust quality and quantity of antibody production to neutralize the COVID‑19 infection, there exists a disconcerting, albeit unintended, possibility: antibody-dependent disease enhancement (ADE). This phenomenon, a dark mirror of vaccine efficacy, could paradoxically increase the virus's attachment to its target cells, potentially triggering a dangerous cytokine storm if a vaccinated individual were later exposed to the wild virus. The risk and extent of ADE are influenced by a multitude of factors, including the specific vaccine technology platform employed (e.g., viral vector vaccine, spike (S) protein vaccine, or protein subunit vaccine), the vaccine dose, the timing of repeat vaccinations for potential recurrence of COVID‑19 infection, and even the age of the recipient, with the elderly potentially facing higher risks. The nature of the antibody response generated by a vaccine is intricately linked to the developmental vaccine technologies, including the precision of its mechanism and the chosen route of administration (intramuscular, intradermal, oral, or nasal).

Prior to the COVID-19 pandemic, ADE had been observed in animal studies involving laboratory rodents that received vaccines for SARS-CoV, the virus responsible for severe acute respiratory syndrome (SARS). This historical precedent naturally led researchers to emphasize the critical need for careful assessment of ADE potential with COVID-19 vaccines. However, as of late January 2022, there had been no observed incidences of ADE with COVID-19 vaccines, neither in trials involving nonhuman primates, nor in human clinical trials, nor following the widespread global use of approved vaccines. A collective sigh of relief, though the vigilance remains.

Trials

Volunteer receives CoronaVac injection during Phase III trial by Sinovac in Indonesia.

In April 2020, the WHO, in its characteristic fashion of issuing blueprints for global action, published an "R&D Blueprint (for the) novel Coronavirus." This Blueprint meticulously outlined a "large, international, multi-site, individually randomized controlled clinical trial." The ambitious goal was to allow "the concurrent evaluation of the benefits and risks of each promising candidate vaccine within 3–6 months of it being made available for the trial." The Blueprint also laid out a Global Target Product Profile (TPP) for COVID‑19, identifying the desirable attributes of safe and effective vaccines. These were categorized into two broad groups: "vaccines for the long-term protection of people at higher risk of COVID‑19, such as healthcare workers," and other vaccines designed to provide rapid-response immunity for new outbreaks. The international TPP team was tasked with several critical functions: 1) assessing the development trajectory of the most promising candidate vaccines; 2) mapping candidate vaccines and their global clinical trials, and publishing a frequently updated "landscape" of vaccines in development; 3) rapidly evaluating and screening for the most promising candidate vaccines simultaneously before they even reached human testing; and 4) designing and coordinating a colossal, multi-site, international randomized controlled trial—famously dubbed the "Solidarity trial" for vaccines. This ambitious trial aimed to enable the simultaneous evaluation of the benefits and risks of different vaccine candidates in clinical trials across countries experiencing high rates of COVID‑19 disease, thereby ensuring swift interpretation and global dissemination of results. The WHO vaccine coalition ultimately held the unenviable task of prioritizing which vaccines would proceed into Phase II and III clinical trials, and developing harmonized Phase III protocols for all vaccines that reached the crucial pivotal trial stage.

For those unfamiliar with the rigorous gauntlet of drug development, Phase I trials are primarily concerned with safety and preliminary dosing, typically involving a few dozen healthy subjects. Following a successful Phase I, Phase II trials then evaluate immunogenicity, optimal dose levels (gauging efficacy based on biomarkers), and potential adverse effects of the candidate vaccine, usually in hundreds of people. A Phase I–II trial, as the name suggests, combines preliminary safety and immunogenicity testing, is typically randomized and placebo-controlled, and aims to pinpoint more precise, effective doses. The grand finale, Phase III trials, involve significantly more participants across multiple sites, invariably include a control group, and are designed to definitively test the vaccine's effectiveness in preventing the disease (an "interventional" or pivotal trial), all while meticulously monitoring for any adverse effects at the optimal dose. It's worth noting that the definitions of vaccine safety, efficacy, and clinical endpoints in Phase III trials could, and often did, vary between different companies' trials. This included nuances like defining the degree of side effects, the precise measure of infection or transmission reduction, and whether the vaccine prevented moderate or severe COVID‑19 infection. For instance, Phase III trials for AstraZeneca's intervention commenced on 28 August 2020 and concluded on 5 March 2021, a timeline that would have been unimaginable just a year prior.

In a continuous effort to keep pace with an evolving adversary, both Moderna and Pfizer initiated trials in January 2022 for vaccines specifically tailored to immunize against the rapidly emerging Omicron variant. The virus, it seemed, was not content to stay still.

Enrollment of participants

Vaccine developers faced a unique and formidable challenge: finding enough participants for Phase II–III clinical trials. The virus, SARS-CoV-2, proved to be a "moving target," with its transmission rates fluctuating wildly across and within countries. This volatile environment forced companies into an intense competition for trial participants. For example, in June, the Chinese vaccine developer Sinovac forged alliances in Malaysia, Canada, the UK, and Brazil as part of its strategy to recruit trial participants and manufacture sufficient vaccine doses for a potential Phase III study in Brazil, where COVID‑19 transmission was, at the time, accelerating. As the COVID‑19 pandemic within China became more contained and controlled, Chinese vaccine developers increasingly sought international partnerships to conduct advanced human studies in various countries, inadvertently creating a fierce competition for trial participants with other manufacturers and the WHO's organized international Solidarity trial.

Beyond the competitive recruitment landscape, clinical trial organizers frequently encountered another significant hurdle: individuals unwilling to be vaccinated due to pervasive vaccine hesitancy or, perhaps more troublingly, a disbelief in the underlying science of vaccine technology and its capacity to prevent infection. This was, to put it mildly, an inconvenient truth for public health efforts.

Furthermore, an insufficient number of skilled team members available to administer vaccinations could severely impede clinical trials. These trials had to overcome numerous risks, including the logistical nightmare of recruiting participants in rural or low-density geographic regions, and ensuring diverse representation across variations of age, race, ethnicity, or underlying medical conditions. The complexities were endless.

The eligibility criteria for AstraZeneca's Phase III trial, for instance, were broad: individuals aged 18 to 130 years, of all sexes, and generally healthy volunteers. Specific inclusion criteria mandated an increased risk of SARS-CoV-2 infection and a medically stable condition. Exclusion criteria, however, were equally stringent, encompassing: 1) confirmed or suspected immunosuppressive or immunodeficient states, 2) any significant disease, disorder, or confounding medical finding, and 3) prior or concomitant vaccine therapy for COVID‑19. Precision, even amidst chaos, was paramount.

Adaptive design for the Solidarity trial

A clinical trial design, particularly one in progress, can be dynamically modified through an approach known as an "adaptive design." This allows for alterations to be made if accumulating data during the trial provides early insights into the positive or negative efficacy of the treatment being tested. The WHO Solidarity trial, an ambitious undertaking involving multiple vaccines in clinical studies during 2020, was designed to leverage this adaptive methodology. Its purpose was to rapidly adjust trial parameters across all study sites as new results emerged. Candidate vaccines could be added to the Solidarity trial as they became available, provided they met predetermined priority criteria. Conversely, vaccine candidates demonstrating poor evidence of safety or efficacy when compared to a placebo or other vaccines would be unceremoniously dropped from the international trial. It was a brutal but necessary culling process.

Adaptive designs, when integrated into ongoing Phase II–III clinical trials for candidate vaccines, offered several distinct advantages. They could potentially shorten trial durations, reduce the number of subjects required, thereby expediting decisions for early termination or success, preventing redundant research efforts, and enhancing the coordination of design changes for the Solidarity trial across its geographically dispersed international locations. Efficiency, it seemed, was the only luxury they could afford.

Proposed challenge studies

Challenge studies represent a highly controversial, yet potentially rapid, method of clinical trial. They involve the intentional exposure of test subjects to the very condition being studied, an approach that can significantly accelerate vaccine development. However, human challenge studies are fraught with ethical dilemmas, primarily because they deliberately expose test subjects to dangers that extend beyond the potential side effects of the substance being tested. Historically, challenge studies have been employed for diseases considerably less deadly than COVID‑19, such as common influenza, typhoid fever, cholera, and malaria.

Recognizing both the potential and the peril, the World Health Organization meticulously developed a guidance document outlining stringent criteria for conducting COVID‑19 challenge studies in healthy individuals. These criteria included thorough scientific and ethical evaluation, extensive public consultation and coordination, careful selection and informed consent of participants, and continuous monitoring by independent experts. Despite the ethical tightrope, in January 2021, dozens of young adult volunteers were indeed deliberately infected with COVID‑19 in a challenge trial conducted in a London hospital, managed under the auspices of the British government COVID‑19 Vaccine Taskforce. Once an optimal infection dose of COVID‑19 was precisely identified, the plan was to test two or more of the candidate COVID‑19 vaccines for their effectiveness in preventing infection. A bold, some might say reckless, approach to accelerating knowledge.

Authorizations and licensure

At the nascent stages of the COVID‑19 pandemic in 2020, the WHO, drawing lessons from the 2013–16 Ebola epidemic, issued a guideline for an Emergency Use Listing of new vaccines. This procedure mandated that any vaccine candidate developed for a life-threatening emergency must be manufactured adhering to Good Manufacturing Practices (GMP) and must complete its development in accordance with WHO prequalification procedures. Standards, even in a crisis, had to be maintained.

Even with the rapid development spurred by the COVID‑19 pandemic, the formal licensure of COVID‑19 vaccine candidates necessitated the submission of a comprehensive dossier of information detailing development and manufacturing quality. In the UK and the EU, companies were afforded a "rolling review process." This innovative mechanism allowed them to supply data as it became available during Phase III trials, rather than waiting to compile the full documentation over many months or even years at the conclusion of clinical research, as was the traditional norm. This rolling process enabled the UK's regulator (MHRA) and the European Committee for Medicinal Products for Human Use to evaluate clinical data in real time, thereby allowing a promising vaccine candidate to be approved on an exceptionally rapid timeline by both the UK's MHRA and the European Medicines Agency (EMA). A rolling review process for the Moderna vaccine candidate was initiated in October by Health Canada and the EMA, and in November, Health Canada also began a rolling review for the Pfizer-BioNTech candidate. Bureaucracy, for once, demonstrated a degree of agility.

Early authorizations in China and Russia

As previously noted, China was among the first to grant authorizations. On 24 June 2020, it approved the CanSino vaccine for limited military use and two inactivated virus vaccines for emergency use in specific high-risk occupations. Russia followed suit on 11 August 2020, announcing the approval of its Sputnik V vaccine for emergency use, though its initial distribution remained somewhat constrained outside of its Phase III trial. In September, the United Arab Emirates approved emergency use of the Sinopharm BIBP vaccine for healthcare workers, with Bahrain granting a similar emergency use approval in November. These early approvals, while swift, often bypassed the more extensive data transparency expected in Western regulatory processes, raising eyebrows among some international observers.

First authorizations of RNA vaccines

In the United States, an Emergency Use Authorization (EUA) is, as the Food and Drug Administration (FDA) itself defined it, "a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID‑19 pandemic." Once an EUA is issued by the FDA, the vaccine developer is still expected to continue the Phase III clinical trial to finalize comprehensive safety and efficacy data, ultimately leading to an application for full licensure (approval) in the United States. However, in mid-2020, significant concerns arose that the FDA might grant a vaccine EUA before complete evidence from a Phase III clinical trial was available. This prospect sparked widespread apprehension about the potential for lowered scientific standards in the face of intense political pressure. In a reassuring, if somewhat performative, gesture, on 8 September 2020, nine leading pharmaceutical companies deeply involved in COVID‑19 vaccine research collectively signed a letter, solemnly pledging that they would submit their vaccines for emergency use authorization only after their Phase III trials had unequivocally demonstrated both safety and efficacy. A promise that, mercifully, largely held.

Pfizer-BioNTech COVID-19 vaccine.

The Pfizer-BioNTech partnership, having completed its pivotal trials, submitted an EUA request to the FDA for its mRNA vaccine BNT162b2 (active ingredient tozinameran) on 20 November 2020. This was the moment many had been waiting for. On 2 December 2020, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) granted temporary regulatory approval for the Pfizer–BioNTech vaccine. This made the UK not only the first country to approve this vaccine but also the first country in the Western world to approve the use of any COVID‑19 vaccine. A historic moment, indeed. On 8 December 2020, 90-year-old Margaret Keenan made headlines as she received the vaccine at University Hospital Coventry, becoming the first person known to be vaccinated outside of a clinical trial as the UK's vaccination programme officially commenced. (Though, it must be acknowledged, other vaccines had been administered earlier in Russia, albeit with less global fanfare). On 11 December 2020, the US Food and Drug Administration (FDA) granted an Emergency Use Authorization (EUA) for the Pfizer-BioNTech vaccine. Just over a week later, on 19 December 2020, the Swiss Agency for Therapeutic Products (Swissmedic) went a step further, approving the Pfizer-BioNTech vaccine for regular use—not just emergency use—after a two-month review. This marked the first authorization by a stringent regulatory authority under a standard procedure for any COVID‑19 vaccine. On 23 December, a 90-year-old Lucerne resident became the first individual to receive the vaccine in continental Europe, a quiet but significant milestone.

By December 2020, numerous countries and the European Union had authorized or approved the Pfizer-BioNTech COVID‑19 vaccine. Meanwhile, Bahrain and the United Arab Emirates had already granted emergency marketing authorization for the Sinopharm BIBP vaccine, showcasing a diverse global approach to initial approvals. In the United Kingdom, a remarkable 138,000 individuals had received the Pfizer-BioNTech COVID‑19 vaccine, known commercially as Comirnaty, by 16 December, during the inaugural week of the UK vaccination programme. On 18 December 2020, the US FDA granted an EUA for mRNA-1273, the Moderna vaccine, solidifying the mRNA platform's dominance in the early stages of the pandemic response. It's an interesting footnote that vaccine manufacturers, in their haste, were still awaiting full regulatory approvals to bestow official, memorable names upon their creations.

Moderna, not to be outmaneuvered, submitted its request for an EUA for mRNA-1273 to the FDA on 30 November 2020. This was swiftly followed by the FDA granting the EUA for the Moderna vaccine on 18 December 2020. The gears of regulatory approval, once notoriously slow, were now turning at an unprecedented pace.

United Kingdom

The UK Medicines and Healthcare products Regulatory Agency (MHRA) continued its rapid authorization streak by granting the first approval to the Oxford/AstraZeneca vaccine on 30 December 2020. This marked its second vaccine to be incorporated into the national rollout under a conditional and temporary authorization to supply. The MHRA provided detailed information for healthcare professionals regarding the COVID-19 Vaccine AstraZeneca, outlining its conditions of authorization and ensuring that the public and medical community were informed of its emergency deployment.

Australia

In October 2020, the Australian Therapeutic Goods Administration (TGA) began its formal assessment process, granting provisional determinations to AstraZeneca Pty Ltd for its COVID‑19 vaccine, ChAdOx1-S [recombinant], and to Pfizer Australia Pty Ltd for its COVID‑19 vaccine, BNT162b2 [mRNA]. These provisional determinations were critical initial steps towards potential approval. Janssen Cilag Pty Ltd followed suit, receiving a provisional determination for its COVID‑19 vaccine, Ad26.COV2.S, in November 2020.

The TGA then moved to grant provisional approval to Pfizer Australia Pty Ltd for Comirnaty on 24 January 2021. This was a significant moment for Australia's vaccination strategy, accompanied by the release of the Australian Public Assessment Report for BNT162b2 (mRNA), providing transparency on the regulatory decision. Subsequently, on 24 June 2021, the TGA granted a provisional determination to Moderna Australia Pty Ltd for Elasomeran, indicating continued expansion of available vaccine options.

European Union

In October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) initiated its "rolling reviews" for two key vaccine candidates: the COVID‑19 Vaccine AstraZeneca (ChAdOx1-SARS-CoV-2) and the Pfizer-BioNTech COVID‑19 Vaccine (BNT162b2). This marked the beginning of a streamlined, yet thorough, evaluation process. The EMA provided regular updates on the status of its rolling review for the COVID‑19 Vaccine AstraZeneca, particularly after the UK granted its temporary authorization, highlighting the interconnectedness of regulatory decisions.

In November 2020, the EMA further demonstrated its proactive stance by publishing a comprehensive safety monitoring plan and detailed guidance on risk management planning (RMP) specifically for COVID‑19 vaccines. This plan meticulously outlined how relevant new information emerging after the authorization and widespread uptake of COVID‑19 vaccines during the pandemic would be systematically collected and promptly reviewed. To ensure transparency, all RMPs for COVID‑19 vaccines were to be publicly available on the EMA's website. The EMA also issued guidance for developers of potential COVID‑19 vaccines, specifying the clinical evidence required for marketing authorization applications. In a parallel effort, the CHMP commenced a rolling review for the Moderna vaccine for COVID‑19, known as mRNA-1273, in November 2020.

By December 2020, the EMA had received formal applications for conditional marketing authorizations (CMA) for both the mRNA vaccines BNT162b2 (Pfizer-BioNTech) and mRNA1273 (Moderna COVID‑19 vaccine). The assessments for these vaccines were fast-tracked, with the ambitious possibility of opinions being issued within weeks. Furthermore, in December 2020, the CHMP began a rolling review of the Ad26.COV2.S COVID‑19 vaccine from Janssen-Cilag International N.V., broadening the scope of its evaluations.

The culmination of these efforts came swiftly. On 21 December 2020, the CHMP recommended granting a conditional marketing authorization for the Pfizer-BioNTech COVID‑19 vaccine, Comirnaty (active ingredient tozinameran), developed by BioNTech and Pfizer. This pivotal recommendation was promptly accepted by the European Commission on the very same day, marking a monumental step in Europe's fight against the pandemic.

Following closely, on 6 January 2021, the CHMP recommended granting a conditional marketing authorization for COVID-19 Vaccine Moderna. This recommendation, too, was accepted by the European Commission on the same day, adding another critical tool to Europe's arsenal.

In January 2021, the EMA received an application for conditional marketing authorization (CMA) for the COVID‑19 vaccine known as COVID‑19 Vaccine AstraZeneca, developed by AstraZeneca and Oxford University. On 29 January 2021, the CHMP recommended granting this conditional marketing authorization, a recommendation that was subsequently accepted by the European Commission on the same day.

The EMA's rolling reviews continued into February 2021, with the CHMP initiating assessments for NVX-CoV2373, a COVID‑19 vaccine under development by Novavax CZ AS (a subsidiary of Novavax, Inc.), and CVnCoV, a COVID‑19 vaccine being developed by CureVac AG. Recognizing the evolving nature of the virus, the EMA also announced in February 2021 that it was actively developing vaccine guidance specifically designed to address the challenges posed by emerging virus variants.

In February 2021, the EMA received an application for conditional marketing authorization (CMA) for the COVID-19 Vaccine Janssen, developed by Janssen-Cilag International N.V. The EMA's recommendation for a conditional marketing authorization of this vaccine was issued on 11 March 2021, and, predictably, it was accepted by the European Commission on the same day.

The regulatory efforts continued unabated. In March 2021, the CHMP commenced a rolling review of Sputnik V (Gam-COVID-Vac), with R-Pharm Germany GmbH serving as the EU applicant. In May 2021, the CHMP expanded its evaluations to include the use of Comirnaty for young people aged 12 to 15, and also initiated a rolling review of Sinovac COVID-19 Vaccine, with Life'On S.r.l. acting as the EU applicant for Sinovac. These continuous efforts underscored the dynamic and ever-expanding nature of vaccine development and authorization in the face of a relentless global health crisis.