Twenty Years of Progress Toward West Nile Virus Vaccine Development

Abstract

Although West Nile virus (WNV) has been a prominent mosquito-transmitted infection in North America for twenty years, no human vaccine has been licensed. With a cumulative number of 24,714 neurological disease cases and 2314 deaths in the U.S. since 1999, plus a large outbreak in Europe in 2018 involving over 2000 human cases in 15 countries, a vaccine is essential to prevent continued morbidity, mortality, and economic burden. Currently, four veterinary vaccines are licensed, and six vaccines have progressed into clinical trials in humans. All four veterinary vaccines require multiple primary doses and annual boosters, but for a human vaccine to be protective and cost effective in the most vulnerable older age population, it is ideal that the vaccine be strongly immunogenic with only a single dose and without subsequent annual boosters. Of six human vaccine candidates, the two live, attenuated vaccines were the only ones that elicited strong immunity after a single dose. As none of these candidates have yet progressed beyond phase II clinical trials, development of new candidate vaccines and improvement of vaccination strategies remains an important area of research.

Animal and Human Vaccines against West Nile Virus

“…Nowadays, effective licensed vaccines, either attenuated (yellow fever, Dengue, and Japanese encephalitis), or inactivated (Japanese encephalitis, tick-borne encephalitis, and Kyasanur forest disease), are available against several flaviviruses. Nevertheless, none has been licensed for human use against WNV, and none of the six vaccines assayed in humans have progressed further than to phase I/II clinical trials [ 31 ]. Even more, only two attenuated recombinant candidates expressing the WNV prM and E proteins, ChimeriVax (in a yellow fever virus backbone) and rWN/DEN4Δ30 (in a truncated Dengue virus 4 backbone), induced strong immunity after a single dose [ 32 , 33 ].…”

Current Understanding of West Nile Virus Clinical Manifestations, Immune Responses, Neuroinvasion, and Immunotherapeutic Implications

“…Since 1999, WNV has been estimated to cause more than 6 million human infections [13], with over 24,000 neurological disease cases and 2300 deaths in the U.S. In addition, in 2018, a large outbreak occurred in Europe involving over 2000 human cases in 15 countries [15]. Therefore, there is an urgent need to understand in-depth the pathogenesis of WNV and develop specific treatment strategies.…”

“…Despite the development of four licensed veterinary WNV vaccines, there are still no approved vaccines or antivirals available for human use. Although several clinical trials have been initiated with multiple vaccine candidates, none have proceeded to the final phases of clinical testing or are even close to meeting U.S. Food and Drug Administration (FDA) approval (reviewed in [15]). The general reasons for the lack of a human vaccine may include scientific challenges (mainly in obtaining protective immunity), safety concerns (including potential antibody-dependent enhancement responses to other flavivirus infections), difficulties in clinical study design (due to lack of enough WNV cases for a phase III vaccine efficacy study), and economic considerations [175].…”

Viral Emerging Diseases: Challenges in Developing Vaccination Strategies

“…For the development of a vaccine for humans, many different platforms were used in preclinical studies, and many of them entered into phase I/II trials, including hydrogen peroxide–inactivated whole virus (HydroVax) vaccine (NCT02337868) ( 103 ), a recombinant truncated form of WNV E protein ( 104 ), recombinant chimeric live attenuated viral vectors, employing YFV ( 105 ), or MVA ( 106 ) delivering WNV prM/E proteins (NCT00442169), pDNA vaccines encoding prM/E (NCT00106769) ( 70 , 107 ). All the Envelope-based vaccines induced NAbs against both WNV lineages 1 and 2, but some candidates are unable to generate long-lasting antibody responses, requiring multiple administrations ( 103 , 108 , 109 ). Thus, further improvements are needed for the development of next-generation vaccines ( 110 ).…”