HONG KONG – The first human trial of a new vaccine based on virus-like particles (VLPs) suggests it is safe and effective against the rapidly emerging mosquito-borne chikungunya virus, researchers reported in the Aug. 15 early online edition of The Lancet.
Since first being identified in Tanzania in 1953, the chikungunya virus has spread beyond Africa to become a growing public health threat affecting 5 million to 10 million people throughout Africa, Southeast Asia, Europe and, most recently, emerging in the Americas.
An arboviral disease transmitted by aedes mosquitos, which are also the vectors for dengue fever, chikungunya virus has become a particular public health problem in Southeast Asia in recent years, with large numbers of cases having been reported in Singapore, Malaysia and Thailand.
"Chikungunya virus has adapted itself to be transmitted by not only the Aedes aegypti mosquito that lives mainly in the tropics, but also by A. albopictus, which is found in more temperate regions," explained study leader Julie Ledgerwood from the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases.
"Since 2006, the virus has caused outbreaks of disease where it had never been previously reported, including Italy, France and, most recently, the USA," she added, noting that to date an effective vaccine has proved elusive.
However, vaccines have been developed against other mosquito-borne pathogens. "There are experimental dengue and malaria vaccines which are undergoing evaluation," said Yuen Kwok-yung, Henry Fok Professor in Infectious Diseases and chair professor of the Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong.
"Currently, we have no licensed vaccines or approved drugs for this debilitating infection [chikungunya virus], which causes fever and intensely painful, severe arthritis," Ledgerwood pointed out.
A live attenuated chikungunya virus vaccine elicited a robust immune response in a 2014 phase II trial, but 8 percent of recipients reported arthralgia and the attenuation was due to just two mutations in the viral E2 envelope protein. Other vaccines have shown promise in mice but have yet to reach clinical trials.
However, unlike earlier vaccine candidates, the new chikungunya vaccine consists of VLPs developed from the outer structural proteins of the West African strain 37997, which would typically be encountered and recognized by the immune system.
The VLPs imitate the immunogenic effects of the actual virus, but they cannot cause infection because they do not contain viral DNA, with earlier research in rhesus monkeys having demonstrated that the new VLP vaccine provided protection from infection.
This is important, as "VLP-based vaccines are generally safer than attenuated vaccines, both for [vaccine] manufacturing workers and for patients, as they are not living so will not revert to virulence as a result of a spontaneous mutation from the attenuated to the virulent state," Yuen told BioWorld Asia.
The NIH phase 1 dose-escalation trial included 25 healthy volunteers, ages 18 to 50, each of whom received one of three different doses of injected vaccine at weeks zero, four and 20, with recipients' serum viral neutralizing antibody titers being assayed at regular intervals.
The vaccinations were well tolerated without serious adverse events or inflammatory side effects, although four participants reported mild to moderate treatment-related side effects, including transient liver enzyme elevations and neutropenia.
Neutralizing antibodies indicating an immune response were detected in the majority of recipients after the first vaccination. Even the lowest doses of the vaccine were effective, and following the second vaccination, all recipients had developed high antibody titers with all vaccine doses. Importantly, antibody titers were sustained and detectable in all study participants six months after the final booster dose.
"Eleven months after vaccination, antibody levels were comparable to those seen in people who had recovered after natural chikungunya infection, suggesting the VLP vaccine could provide long-term protection against the virus," Ledgerwood said.
Yuen pointed out, though, that other protective measures also may be important in protecting against mosquito-borne epidemics such as chikungunya virus.
"Vaccines are important, but mutant viruses may emerge and lead to outbreaks over time," he explained. "Thus, other control measures such as personal protection using DEET-impregnated clothing and nets, and mosquito control are important complementary [prevention] measures."
THE COST OF DEVELOPMENT
However, while the new chikungunya VLP vaccine candidate looks promising, prohibitively high vaccine development costs may ultimately prevent its development, as has proved to be the case for certain other promising vaccines.
For example, while a number of candidate vaccines have been developed that successfully protected monkeys from multiple strains of the deadly Ebola virus, which is currently endemic in West Africa, those vaccines never entered human clinical trials.
Although the NIH and U.S. government frequently finance early animal safety and efficacy testing of new vaccines, pharmaceutical companies usually fund the extremely expensive human clinical trials necessary to take a new vaccine to market.
"Development of vaccines for orphan agents is challenging, because the market might not be large enough to justify the investment," noted Ann Powers, from the U.S. Centers for Disease Control and Prevention in an accompanying Comment in The Lancet.
"The cost of development of a vaccine from preclinical studies to vaccine registration is estimated to be $200 million," she said. Nevertheless, "even with this need for substantial funding, vaccines are still the most cost-effective strategy for disease prevention."
"In view of the burden of chikungunya outbreaks, which have affected up to 63 percent of local populations in a matter of months, the continued development of this VLP vaccine candidate . . . should be encouraged."