On 19 January 2023, Janssen and Partners announced the discontinuation of the phase 3 Mosaico HIV vaccine clinical trial because evidence of efficacy was lacking. Another HIV vaccine efficacy trial and another disappointment. Remarkably, there have been only nine such trials in the past 40 years; although none have successfully led to a vaccine, they have contributed to our understanding of HIV/AIDS and the development of other vaccines, for example, COVID-19 vaccines.

Where to from here? As AVAC’s Mitchell Warren puts it “I’m not sure we know exactly where the next big investment is going to come from because there’s not an obvious vaccine candidate in HIV that is next up in our efficacy pipeline”.

But beyond product development, the larger question of investment in HIV prevention and vaccine research arises. There are now several other effective prevention tools available, and current funding could be used to refine tools, improve delivery, facilitate access, and increase uptake. Some in the HIV field, as well as outside it, were already asking that question before MOSAICO’s termination. They may now feel vindicated by the time and money it will take to conduct another vaccine efficacy trial.

It is true that prevention has made tremendous progresses in the last 10 years with U=U, PrEP, Long-Acting PrEP, and the vaginal ring. Where will we be in 10 years when a candidate HIV vaccine might be ready to enter efficacy testing? PrEP as yearly implants, as weekend patches? Why not a microbicide? Ten years is a reasonable timeframe for improving current technologies, improving access, reducing cost of prevention and care, addressing stigma and discrimination that limit access. Where will a vaccine fit in this future?

Further, there are many questions and uncertainties around the development of an HIV vaccine beside the many scientific challenges. Will we have resolved the teething problem of conducting efficacy trials in the context of effective prevention and improved standards of care? Who will want it? What shape and form will it needs to be to have an impact?

We should not shy away from these questions or brush them aside. We should not disregard the possibility of a brighter future where they may be no need for a vaccine, or an even brighter one where there could be one showing efficacy at last. But we are not there. We need to address current concerns and provide convincing answers if we want HIV vaccine R&D to continue and be successful.

We can lament the lack of industry involvement, ignore the endgame – it is so far away. We can continue to work on antigen design, immunization regimens and new platforms, but this is not all that we can do. We have been there before. How often have we heard about promising vaccine candidates entering trials and of encouraging findings in first-in-human clinical trials evaluating new approaches? But as products failed, followed by sorrow, introspection, call for change, optimism that next time will be the time, we carry on picking up from where we left at the last failed revolution, rushing into the next scientific tunnel, like meerkat towards a cliff.

We should definitively continue to support vaccine R&D – this is where the commitment is now, but that is only a third of the job. The second third is to make the case that an HIV vaccine will still have a role and a place in 10-years’ time. And the last third is to reignite a grass root movement that seem to have disappeared since the advent of other prevention tools, to call for an HIV vaccine, as we have seen for PrEP.

With rising number of HIV infections in several countries, settings and populations, our collective recurrent failure to reach prevention and treatment targets (from 3×5 to 90-90-90), limited access and cost of modern effective prevention (not to mention the impact of conflicts and other pandemics), there are many reasons for pursuing a vaccine.

In many ways HIV has been exceptional but has also fallen victim of this exceptionalism. It has been over forty years since the promise of an HIV vaccine entering clinical trial within 2 years, of paradigm shifts, of the field hopping from enthusiasm to defeat. This exceptionalism is starting to wear out some funders now asking for a more integrated, horizontal, global approach, if not for a global plan for a vaccine.

The future of HIV vaccine R&D will be bleak unless we change how we approach it. We need to understand the needs, find the edges, innovate beyond science, to include funding and ways of working, and critically, create a demand for a vaccine. There are ways, there is funding, there is will, so, what’s missing for a transformative paradigm shift?