Forging the Path to a West Nile Vaccine

In this video, Carolyn Gould, MD, of the Division of Vector-Borne Diseases at the CDC, discusses her recent New England Journal of Medicine perspective piece, “Combating West Nile virus disease — Time to revisit vaccination.” In the article, Gould and colleagues address challenges to the creation of a West Nile virus vaccine for humans.

The following is a transcript of her remarks:

Since West Nile virus was first detected in the United States in 1999, it has become the leading cause of mosquito-borne disease, causing more than 55,000 reported cases of human disease and over 2,600 deaths. West Nile virus can cause severe illness including meningitis, encephalitis, and acute flaccid paralysis. Those who survive are often left with long-term neurologic and functional sequelae.

Because of the seriousness of the disease, there’s a very large cost burden associated with West Nile. For example, in California, West Nile hospitalizations cost almost $60 million a year, and that doesn’t include post-acute care, medical costs, and loss of productivity. So it’s a big problem.

Over the last 2 decades since West Nile was introduced into the United States, despite our best efforts to prevent infections through things like community mosquito-control programs and personal protective measures, we’re still seeing high numbers of cases most years, and unprecedented and unpredictable outbreaks of disease.

For example, in 2021, Maricopa County, Arizona experienced the largest outbreak of West Nile disease on record with more than 1,400 cases, 1,000 hospitalizations, and over a 100 deaths reported, and this was recently highlighted in an MMWR [Morbidity and Mortality Weekly Report] publication.

Throughout the country in 14 of the last 20 years, we’ve seen more than 2,000 cases a year reported, if not more; often in other outbreak years, there have been 5,000 to 9,000 cases reported. So we need to do more than we’ve been doing, and that means revisiting the development of West Nile vaccines.

We outlined several reasons why efforts to develop human West Nile vaccines beyond phase I and II clinical trials have stalled.

The first is the problem of designing phase III clinical trials needed for vaccine licensure. Phase III trials ideally are large double-blind, placebo-controlled studies and [with] populations at high risk of disease with clinical endpoints such as prevention of disease and death. Designing phase III clinical trials for West Nile vaccines is challenging because of the unpredictable and sporadic nature of disease outbreaks, which makes it difficult to select the geographic location for the trial. So if the incidence rate is low in the selected area and we’re vaccinating only a subset of the population, namely persons who are 50 years or older, it could take years to enroll enough patients to complete the trial and demonstrate clinical efficacy. This has certainly been a major deterrent in trying to design large clinical trials for West Nile vaccines.

The second challenge we identified has been the potential safety concern. Some of the West Nile vaccine candidates are live attenuated chimeric vaccines, and as with all live vaccines, there’s a greater risk of adverse events in patients who are older or who have compromised immune systems. Since older populations would be the target for West Nile vaccines, there are concerns about safety in this group.

The third challenge has been the perceived costs of West Nile vaccination. Previous cost-effectiveness studies have suggested that the cost of hypothetical national or age-based West Nile vaccine programs was not favorable.

So those are some of the challenges that led to the development of West Nile vaccines stalling about 14 years ago. We do think that it’s possible to overcome these barriers. So for example, we’re in a better position now to pursue alternative pathways to licensure compared with when the early clinical trials of West Nile vaccine candidates were completed. For instance, we now have four licensed flavivirus vaccines. West Nile is a flavivirus in the United States, so we’re not starting from scratch. Just as an example, approval of the Japanese encephalitis vaccine was done using an established immune-correlative protection, which basically is a specific level of antibody titer that is known to protect against disease rather than using clinical endpoints like disease and death.

Using a similar approach for West Nile vaccines could help us identify a safe and effective vaccine outside of the traditional phase III clinical trial model, and there are other alternative pathways as well that could be considered.

Regarding safety, no vaccine-related adverse events were identified in early clinical trials of any of the vaccine candidates, including the live vaccines, even in older participants. But these early clinical trials involved relatively small numbers and are not designed to detect very rare adverse events, so we do need additional assessments of safety, but at least early results are promising.

Finally, although previous modeling studies suggested that the cost of West Nile vaccination was high, a recent analysis of a program targeting older persons in high-incident geographic areas found that the cost estimates were actually much more reasonable than previously thought.

We haven’t seen any decline in West Nile cases over the past 20 years, and in fact, we continue to see these large, even unprecedented outbreaks resulting in severe disease and death. These outbreaks keep occurring despite our best effort. So we hope this article is a catalyst to start discussions between our partners and stakeholders that could bring safe and effective West Nile vaccines to market.

We have four veterinary vaccines that are licensed; we do not have any human vaccines. The last time a West Nile vaccine completed phase II clinical trials was 14 years ago. So, we’re at a better place now to consider alternative approaches to vaccine licensure given we have more experience with alternative pathways to licensure for other vaccines that have come out since then.