There has been a lot of talk about vaccine nationalism – the practice of countries hoarding limited vaccine supplies – and the risk it presents to global efforts to end the COVID-19 pandemic. This risk is very serious and real, and in recent weeks has been compounded by the impact of vaccine hesitancy – particularly hesitancy related to rare blood clotting events linked to the AstraZeneca vaccine. New evidence suggests that this particular driver for vaccine hesitancy is delaying vaccine delivery in certain countries and is also affecting advanced purchase agreements (APAs) for vaccines. As such, it presents a much more potent and immediate risk to successful COVID-19 vaccine rollouts globally than vaccine nationalism on its own could have ever produced.

Safety concerns affecting AstraZeneca and Johnson & Johnson vaccines

In the week starting on 12 April, concerns about a potential link between adenovirus-based vaccines, including AstraZeneca (UK)’s Vaxzevria (formerly known as AZD1222) and Johnson & Johnson (US)’s Ad26.COV2-S, have affected vaccine delivery. The rollout of the J&J vaccine has been voluntarily suspended by the company in Europe and is also on hold in the United States pending completion of the FDA’s investigation into blood clotting events following vaccination. The European Medicines Agency is currently examining the evidence and is due to issue its recommendation on Ad26.COV2-S safety next week. AstraZeneca’s vaccine remains under scrutiny as well. While some countries had already restricted the use of Vaxzevria in younger age groups, this week Denmark became the first EU country to completely stop using it in its vaccination program.

Risk of vaccine hesitancy spilling over into other adenovirus-based vaccines

The discovery of a potential biological mechanism for the link between vaccination with adenovirus-based vaccine and extremely rare cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) will likely continue to drive vaccine hesitancy in relation to the AstraZeneca vaccine. It is possible that the same mechanism will apply to other adenovirus-based vaccines, including J&J’s Ad26.COV2-S, Gamaleya Institute (Russia)’s Sputnik V and CanSino (China)’s Convidecia (formerly Ad5-nCOV), and as a result their use could also be impacted. The incidence of cerebral venous thrombosis (CVT) is extremely rare – about 5 cases per million observed in those who have received Vaxzevria, compared to 4 per million for Pfizer (US) or Moderna (US) mRNA vaccines, and 39 per million in people who actually develop COVID-19 disease, according to a newly-released University of Oxford study.

The risk of CVT is extremely low and certainly lower than the risk of COVID-19 itself, but relentless coverage of the side effect risks in the media and the sometimes ill-informed comments from politicians are taking their toll on public confidence. If a single vaccine is implicated and there is a sufficient supply of alternative vaccines, the impact may be less significant. However, AstraZeneca’s vaccine accounts for the bulk of the global vaccine supply under COVAX. It is also the most affordable of the available COVID-19 vaccines at present. If the rare side effect link is confirmed for other adenovirus-based vaccines, and the media frenzy and resulting vaccine hesitancy reach similar levels, global vaccination efforts will stall. J&J’s vaccine – the only one requiring a single dose – would be particularly useful for vaccinating hard-to-reach population groups. Gamaleya’s Sputnik V has the highest number of regulatory approvals globally after AstraZeneca’s vaccine. Undermining confidence in all three of these vaccines – and by implication, other COVID-19 vaccines where CVT effects have also been observed – could result in unfortunate situations where precious vaccine quantities are delivered and are left to expire due to low uptake – while all the while thousands of people continue to die from COVID-19 daily and new virus variants emerge.

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Impact on vaccine delivery and APAs

Some of the effects of vaccine hesitancy are already evident. This week, Latvia and Lithuania asked Denmark to sell them leftover doses of Vaxzevria and, in recent days, opened walk-in vaccination centers offering surplus doses of the AstraZeneca vaccine to young people after some of the people in priority groups did not attend vaccination appointments. Meanwhile, Vietnam is attempting to speed up vaccination before Vaxzevria doses delivered by COVAX expire. Malawi has had to destroy 16,000 expired Vaxzevria doses, citing vaccine hesitancy concerns as the reason for low vaccination uptake.

Looking at the medium- and long-term, vaccine hesitancy related to adenovirus-based vaccines may affect countries’ appetite for entering APAs for particular vaccines. Australia’s government this week decided not to purchase doses of the J&J vaccine, despite a lack of firm evidence linking it to VITT. Meanwhile, Italian news source La Stampa has quoted undisclosed EU officials as saying that the European Commission is unlikely to renew APAs or enter new contracts for vaccine supply with either AstraZeneca or Johnson & Johnson in 2022. In a bid to boost access to alternative vaccines, the European Commission has started negotiations with BioNTech and Pfizer for a third APA contract to supply an additional 1.8 billion doses of Comirnaty during 2022 and 2023.

There may be a benefit for mRNA vaccines in the short term – in terms of increased demand – if public confidence in adenovirus-based vaccines is dented. In the medium- and long-term, however, we all lose, as the cost of inciting vaccine hesitancy is measured in lives lost, delayed economic recovery, and widening inequity at the global and national level.