COVID-19 vaccines: the start of a new era in regulation?

The global COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‑CoV‑2) has challenged regulators to reevaluate longstanding paradigms of vaccine development. Although the urgent need for expedited vaccine development against viral pathogens has occurred in past epidemics (e.g. Ebola virus Zaire) and in prior pandemics (e.g. H1N1 influenza), these situations were not completely analogous [1,2]. Specifically, the outbreaks were either limited in the extent of their spread (i.e. Ebola) or were caused by agents that were reasonably closely related to known pathogens for which there were existing model vaccines available (i.e. H1N1 influenza). For SARS-CoV-2, although the pathogen was rapidly identified as a member of the coronavirus family that included SARS-CoV-1 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), it was rapidly spreading globally at the time vaccine development was initiated. Additionally, there were not well established safe and effective vaccines against closely related viral pathogens already available. Therefore, an expedited approach to the development of novel vaccines was necessary.

In setting out to rapidly develop such new vaccines, it quickly became apparent that it would be important to follow certain principles. First, it was essential that potential vaccine developers understood the safety and efficacy profiles that were to be targeted with these new vaccines. Second, the pathway forward toward providing access to a broad population needed to be clarified. Third, an amalgam of previous time saving efforts needed to be made to ensure timely vaccine investigation and commercial scale production. Fourth and finally, the ability to resolve any issues potentially adversely affecting the efficiency of vaccine development in real time was quite critical.

The ultimate timely success of vaccine development and production rested on the fact that all four of these issues were effectively addressed. The issuance of FDA guidance documents addressed the expectations for safety and effectiveness as well as how access would be provided. The guidance Development and Licensure of Vaccines to Prevent COVID-19 first issued in April 2020 provided clear expectations for industry regarding the expectations of scale of the clinical trials that would be required and set forth the minimum expectation for effectiveness for disease prevention of 50% with a lower bound of the 95% confidence interval of 30% [3]. Because of the effort involved in deploying a new vaccine in a population of many millions of individuals, there was concern that lower effectiveness would lead to poor acceptance of the vaccine and have an inadequate positive impact during the pandemic. A second guidance, Emergency Use Authorization for Vaccines to Prevent COVID-19, first issued in October 2022, and made clear the path toward availability of vaccines under Emergency Use Authorization (EUA) [4]. It also set forth the need for a minimum of two months median follow-up for any new vaccine submitted for an EUA. The median two-month period for follow-up was chosen as a reasonable compromise for safety assessment during a pandemic taking hundreds of lives daily: about 95% of rare serious adverse events that may be attributed to vaccines become apparent within 45 days of vaccination [5]. This guidance also noted the need for enhanced post-authorization pharmacovigilance monitoring. The ability to conduct such monitoring was facilitated in part by the preexisting availability of large healthcare safety databases [6–8].

In the setting of such guidance, those in industry and government working to develop vaccines set out to condense the development and manufacturing process, in large part, by eliminating optional or unnecessary delays. These included, in some cases, collapsing the phases of clinical trials into Phase 1/2/3 trials and scaling up manufacturing at risk, so that if a vaccine ultimately proved effective in clinical trials that were completed, there would be adequate product available to initiate a mass vaccination campaign.

Finally, and perhaps most importantly, there was a focus on timely communication. The standard Type A, B and C meeting timelines associated with a wait of up to a 30 to 75 days for sponsors developing products to have scheduled meetings take place with the FDA were set aside, and a policy of constant contact was implemented for the leading vaccine candidates moving through development. In some cases, complicated questions posed by developers in the morning were answered by day’s end, sometimes following impromptu teleconferences with those developers, facilitating clarification of the questions asked. This particular aspect of the facilitation of COVID-19 vaccine development may have the most long-lasting effect on the development of a wide range of medical products, as the benefits of such free-flowing communication in speeding product development became eminently clear.

The successful completion of the clinical trials programs for the two mRNA vaccines and one adenoviral-vectored (Ad26) COVID-19 vaccine was soon followed by a rollout that revealed some of the challenges in the widespread launch of new vaccine platforms. For the mRNA vaccines, rare anaphylactic reactions and then myocarditis, primarily in younger males were identified as safety signals [9,10]. For the adenoviral-vectored COVID-19 vaccine, the identification of the very rare event of thrombosis and thrombocytopenia syndrome (TTS) transiently halted vaccination [11]. All these relatively early findings, as well as others, confirmed the importance of a robust safety surveillance system as being of essential importance to regulators responsible for the safe deployment of vaccines. Having a ready means of conducting large-scale safety surveillance has clearly become an integral part of being able to appropriately regulate the rapid deployment of novel vaccines moving into the future. In addition to safety surveillance, the ability to assess vaccine effectiveness is highly desirable, and the systems that facilitate safety evaluation can potentially be additionally utilized for the determination of vaccine effectiveness as it evolves during an outbreak.

And vaccine effectiveness certainly has evolved during the pandemic. Within several months after the deployment of the vaccines against COVID-19 that appeared to be highly effective, it became apparent that two concomitant phenomena were occurring: there was a waning of immunity, particularly apparent in older individuals, and as or more significant, it became apparent that the virus was rapidly evolving and that new variants might be more resistant to the immunity provided by the current generation of vaccines [12]. This became eminently clear with the evolution of the Omicron variant from BA.1 into BA.4 and BA.5 and more recently its further evolution to BQ.1 and BQ.1.1 and XBB. This evolution highlights the need for an improved generation of COVID-19 vaccines [13].

However, in the interim, the need to address the emerging variants has forced regulatory agencies to develop a level of comfort with vaccine platforms, such as mRNA technology, to allow them to keep up with SARS-CoV-2 using existing technology. Thus, in the United States, bivalent Omicron BA.4/BA.5 plus original mRNA COVID-19 vaccines were authorized for use under EUA based on the accrued data compiled with the mRNA COVID-19 vaccine platform, data obtained using prior bivalent COVID-19 vaccines, and non-clinical data [14]. Initial data validating the safety and effectiveness of this approach has recently appeared [15]. Such reliance on prior work with a well-understood vaccine platform may be necessary for further modifications of the COVID-19 vaccines and may also be applicable to other vaccines in the future.

In summary, certain principles implemented during the COVID-19 pandemic may have implications for the future of the development of vaccines and possibly other medical products, ushering in the start of a new era in regulation. Use of well-defined vaccine platforms, enhanced formal communication of expectations through timely formal guidance and well as ongoing informal dialogue between developers and regulators, and the implementation and reliance on robust post-authorization or post-licensure surveillance for safety and effectiveness may notably expedite the vaccine development process. Obviously, all the above approaches must remain solidly based in the available scientific evidence if we are to combat vaccine hesitancy and maintain the type of trust in vaccines that is essential for successful vaccination campaigns. Vaccines have been among the most effective interventions ever introduced in support of public health, and it is our obligation to ensure that their regulation evolves to address the challenges of our time, while ensuring the soundness of their quality, safety, and effectiveness.

Declaration of interests

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This paper was not funded.