Early Vaccine Development: The Challenging Case of the West Nile Virus

NEW TECHNOLOGY has spurred advances in medicine, including the development of vaccines against problematic pathogens. However, despite those breakthroughs, not every promising vaccine has made it to market. One example is the West Nile virus (WNV) vaccine. Efforts to create vaccines to control the virus have stalled at the Phase II level, an illustration of the challenges of early vaccine development. 

What is WNV?

WNV, a member of the flavivirus family, is a growing health challenge in the U.S. and Europe, driven by climate change. Spread by the Culex mosquito and migratory birds, WNV reached the U.S. in 1999; by 2003, it was a major arthropod-borne disease.¹

While 80 percent of infections are asymptomatic, 20 percent result in a febrile illness characterized by fever, muscle aches and gastrointestinal complaints.² Less than one percent of infections cause serious neuroinvasive diseases like meningitis, encephalitis and acute flaccid paralysis.^1,3

From 1999 to 2021, there have been 55,000 reported cases of WNV in the U.S., with 27,000 of them neuroinvasive and 2,600 leading to deaths.⁴ Most neuroinvasive cases are in the north-central to south-central U.S.⁵ 

Unfortunately, new tools to combat WNV have not been developed since its emergence in the northern hemisphere. Prevention is limited to personal protective measures such as clothing and insect repellent, which can be effective but have low adherence. Chemical mosquito control efforts are available in less than 60 percent of U.S. counties, with variable capabilities and coverage.²

A vaccine solution is an unmet need. 

Early Vaccine Development

The COVID-19 pandemic accelerated a trend away from traditional vaccine approaches toward newer modalities. Classical approaches were difficult to scale and had long development times; newer technologies are more adaptive, scalable and agile.⁶

Advances in RNA stabilization, lipid nanoparticle delivery systems and mass production led to breakthroughs with messenger RNA (mRNA) technology.⁶ However, challenges include the need for ultracold storage, variable expression profiles and rare immune-mediated adverse events.⁷

Traditional approaches included inactivated, live attenuated and toxoid-based vaccines. Inactivated vaccines are whole pathogens rendered non-replicative (“killed”) by chemical agents such as formaldehyde, heat or radiation.⁶ Examples are the inactivated poliovirus or hepatitis A vaccines. Live attenuated viruses are weak, replicative strains lacking complete virulence.⁶ Examples are measles-mumps-rubella and oral poliovirus. Toxoid-based vaccines use killed bacterial exotoxins that preserve immunogenicity while eliminating toxicity.⁶ Examples include the diphtheria and tetanus components in the diphtheria-tetanus-pertussis (D-T-P) vaccine.

Bridging the gap between traditional and new technology are the recombinant DNA vaccines. Recombinant vaccines feature peptides or proteins from the pathogen that are produced in a cell factory, such as yeast, insects or mammalian cells. They may also be created as pathogen subunits, such as surface or viral envelope proteins, presented as antigens.⁶ An example is the hepatitis B surface protein vaccine.

The newest technology includes viral vectors, mRNA vaccines and DNA vaccines. Viral vectors are modified viruses used as carriers coding protein antigens such as the Johnson & Johnson COVID-19 vaccine.⁶ mRNA vaccines present synthetic mRNA encoding a target antigen to host cells, where it is expressed and recognized by the immune system.6 Examples include the Moderna and Pfizer-BioNTech COVID-19 vaccines. DNA vaccines, meanwhile, introduce circular plasmid DNA that codes a target antigen through mRNA.⁶ They have been studied in the context of the Zika virus, HIV and COVID-19.

Recent advances in the development pathway, such as the ability to manufacture mRNA and DNA vaccines, have sparked innovation in the field. But not every vaccine has been a beneficiary. 

WNV Vaccine Pipeline

Sometimes, the development pathway is not the bottleneck for a new vaccine. It may be logistics.

While seven vaccines have been developed and tested for WNV, none have advanced past Phase II in the U.S. Food and Drug Administration (FDA) pipeline.¹

Among those studied to date are the following:

• Chimerivax-WN02: a chimeric live attenuated virus with seroconversion above 90 percent after a single dose in clinical trials, including one in Phase II.4,8 This vaccine program is no longer active.²
• WN/DENV4-3’Δ30: a live attenuated chimeric vaccine that showed seroconversion between 65 and 95 percent based on dosing schedule.^4,8 The National Institutes for Health developed it and is awaiting a commercial partnership to enter Phase II.²
• Two DNA-based candidates (WRC-WNVDNA-017-00 and VRC-WNVDNA020-00-VP) showed strong neutralizing antibody responses and seroconversion rates exceeding 96 percent after a three-dose regimen.^4,8
• A recombinant subunit WN-80E/SLA-LSQ, which has shown neutralizing antibody response and safety in a preclinical setting and is awaiting a Phase I trial.²
• Inactivated whole virus formulations have been studied; one has a moderate seroconversion rate (31 to 50 percent) after two doses, and another, a formalin-inactivated vaccine, peaked after a booster dose.⁸

Ironically, WNV vaccine development for veterinary use has been available since 2001.^1,2 These vaccines are effective at reducing infection, morbidity and mortality in animals like horses.²

Barriers to Traditional Trials in Humans

Scientific, safety and economic obstacles have prevented WNV vaccine candidates from advancing to Phase III trials in the U.S.⁴

The unpredictable course of infection outbreaks makes it difficult to assess vaccine efficacy.4 Finding a region with endemic levels of the disease would be preferred; however, even in regions of high incidence, such as Maricopa County, Ariz., the number of cases may vary by year. In 2021, for example, Maricopa reported 1,400 WNV cases and 100 resulting deaths, compared to three cases the previous year. Low case counts and the need for ethics approval for Phase III trials may result in enrollment that takes years to complete. As a result, the traditional pathway may be time-consuming and expensive for potential vaccine manufacturers.⁴

Factors that influence reporting rates also include changes in bird or mosquito populations, weather patterns, the time people spend outdoors and healthcare-seeking behavior.² The most consistent predictor of future WNV cases is past incidence, even though it is inconsistent.⁹ The fact that most diseases are asymptomatic or mild in nature also limits the number of case reports.

Finally, cost-effectiveness is a concern. One study found that vaccinating the general public against WNV was not cost-effective, although targeting older adults may be worthwhile.¹⁰

Nontraditional Approval Options

If Phase III trials prove to be too costly or difficult to implement, options exist. The possibilities were discussed at a one-day Centers for Disease Control and Prevention meeting in April 2024, specifically addressing WNV and vaccine issues.²

Among the options are the following:⁴

• Using surrogate endpoints like immune protection in animal models to argue for the value of the WNV (as has been done with chikungunya vaccines)
• Comparing immunological markers with other flaviviruses, like the Japanese encephalitis vaccine
• Approving an FDA investigational new drug application with an expanded access system
• Creating an emergency use authorization, like those used for early approval of COVID-19 vaccines

WNV vaccines may be candidates for the expedited programs due to their ability to address unmet needs in morbidity and mortality prevention.²

Safety with WNV Vaccines

Even if approved, WNV vaccines may cause safety concerns. The use of live vaccines in older adults and the immunocompromised may lead to reactivation if not handled carefully. For inactivated options, the need for multiple doses and boosters may be an obstacle. Veterinary WNV vaccines, for example, require a two-dose primary series and annual boosters.⁴

Future Outlook

Current prevention strategies continue to be insufficient to control the morbidity and mortality associated with WNV. Overcoming the obstacles that have stalled the early development of a WNV vaccine is crucial to controlling the impact of the disease.