Equipoise regarding relative efficacy

Perhaps the most compelling reason to engage in a secondary vaccine trial would be that there is genuine equipoise concerning the relative efficacy of the existing and candidate vaccines. In some cases, the first successfully licensed vaccine may confer immunity to some, but not all, vaccinated individuals. In such a situation, the efficacy of a candidate vaccine could possibly surpass that of the existing one, creating the potential for genuine equipoise. The ethical viability of such an argument from potentially improved efficacy depends on a variety of factors: the estimated efficacy of the existing vaccine; plausible reasons to think that the candidate might be superior and the public health importance of obtaining a better vaccine.

The higher the estimated efficacy of the existing vaccine, the lower is the likelihood that a secondary trial would lead to an improved product. In the case of Ebola, for example, the Merck vaccine was shown to be effective as much as 97.5% of the time, which meant that it was rather unlikely that the J&J vaccine would have considerably greater efficacy.12 By contrast, in cases where existing vaccines are effective in much less than 100% of patients, the efficacy-argument for a secondary trial may be stronger. When considering efficacy, researchers must also account for any compelling reasons to believe that a candidate vaccine might offer gains to efficacy. These reasons could include theoretical immunological arguments or evidence from head-to-head comparisons of efficacy conducted with nonhuman primates. In the absence of such arguments, the efficacy-based case for a secondary trial is weakened, and it may be implausible to argue for genuine equipoise between the existing and candidate vaccines.

Since the most plausible argument for a secondary trial will often take the form of a consequentialist appeal to the overall societal benefits of obtaining a vaccine with improved efficacy, researchers must consider the scope of these potential benefits to determine whether they outweigh the reasons against conducting a trial. This argument will apply with particular force in the case of pathogens that pose pandemic threats such as COVID-19, and especially for pathogens that have the potential to radically affect the trajectory of human civilisation.26 27

Vaccine characteristics beyond efficacy

While efficacy may be the most salient characteristic of a vaccine and the primary focus of phase III trials, it is not the only important factor when comparing an existing vaccine with a potential candidate. Another such factor is the estimated length of immunity conferred by the respective vaccines. Some vaccines, like the one for measles, offer life-long immunity in almost all vaccinated individuals. Others, like the one for pertussis, offer more limited immunity and requires booster shots at regular intervals or before particular events, such as travel or pregnancy. If the duration of immunity conferred by the existing vaccine is considered too short, a secondary vaccine may represent an opportunity to improve the overall protection of communities. In the case of the Ebola vaccines, the potential for longer lasting immunity has been voiced as a reason to investigate vaccines beyond the Merck shot.28

Another important immunological characteristic is the reactogenicity of the vaccine; that is, how likely it is to produce adverse immunological responses and symptoms that are harmful, but mild enough not to be disqualifying from a safety perspective. If a vaccine is prone to cause symptoms like fever or soreness, this is both harmful to individual patients and it also complicates general preventive vaccination programmes for at-risk populations. Consequently, a novel vaccine candidate with potentially reduced reactogenicity may present an improvement in terms of both general welfare benefits and in terms of realising the core medical ethical principle of non-malevolence.

Beyond effects on the human body, there are other characteristics of a novel vaccine that may make it an attractive alternative to the existing product. For example, a candidate vaccine may hold the promise of being easier to store in a cold chain. Alternatively, it may have advantages in terms of ease of administration to patients; for example, by being administered in one, as opposed to two doses. Since these factors directly affect access to care and can be ascertained before conducting a phase III trial, there is a clear onus on vaccine developers to demonstrate that their candidate offers a valuable addition to the epidemic response arsenal.

Economic and logistical factors

Another class of arguments relate to the production and distribution of vaccines, rather than to the medical countermeasure itself. During the recent Ebola outbreak in the DRC, proponents of the J&J trial raised concerns about a potential shortage of the existing Merck vaccine.15 While it is unclear whether these concerns were substantiated—forecasts made in January suggested that supplies were expected to be sufficient29 and expert witnesses at a congressional testimony in July denied concerns about a shortage30—there is a certain appeal to the general argument that a novel candidate could offer a strict improvement for anyone who otherwise would receive no vaccine at all due to presumed scarcity. In addition to concerns about shortages, proponents of a secondary vaccine trial may also argue that it is critical to have multiple producers responsible for vaccines against the same epidemic diseases, for the sake of both supply chain security and pricing concerns.16 First, they may argue, having multiple producers makes the vaccine supply more robust to disruptions in the event of an emergency. Second, the existence of a competing manufacturer may be welcomed from a perspective of avoiding excessive monopoly pricing. Given these considerations, the argument goes, secondary vaccine developers should be allowed to trial their candidate, so that the arsenal of medical countermeasures against a given disease may be expanded.

These arguments are certainly appealing insofar as they are grounded in legitimate concerns pertaining to equitable access to care as well as global health security. Given that production for many of the most important vaccines is concentrated in a very small selection of facilities, it is desirable to reduce the fragility of the supply by relying on multiple manufacturers. Moreover, since vaccine affordability is a key challenge for global health equity, the prospect of avoiding monopoly pricing may also be important. However, what each of these concerns have in common is that they are economic and logistical challenges which can often be addressed through economic and logistical solutions that pose fewer moral concerns. Indeed, for each of the challenges, it is not obvious that the appropriate solution would be to develop an entirely new product. To avoid shortages during an active outbreak, governments can invest more heavily in procuring robust vaccine supplies prior to and during outbreaks. To mitigate concerns over vaccine supply fragility, governments can work to facilitate licensing agreements between multiple manufacturers. Indeed, two different manufacturers currently produce what is essentially the same cholera vaccine. Similarly, pricing concerns can be addressed through other policy solutions that already exist (such as the Advance Market Commitment),31 or have been proposed in recent years (such as the Health Impact Fund).32 To be sure, policy-based solutions will often be costly and can in some cases sacrifice some of the efficiency that can be associated with purely market-based production and distribution of goods. However, given the strong prima facie reasons against trialling secondary vaccines during epidemics, it stands to reason that policy-based solutions should be considered carefully before turning to the technical solution of aiming for an entirely new vaccine.