Results from phase 1 trials of two different types of Zika vaccines, one of them an inactivated vaccine recently shelved by Sanofi over shaky research support and other challenges, found that they were safe and immunogenic.
One of the studies focused on two different version of a DNA-based vaccines, while the other detailed findings for the inactivated vaccine. Work on both vaccine was done with support from the National Institute of Allergy and Infectious Diseases (NIAID), and both studies were published yesterday in The Lancet.
A dramatic fall in Zika cases prompted the US government to reshuffle its Zika-related research priorities. About 2 month ago, Sanofi announced it was halting work on its candidate inactived Zika vaccine in the face of scaled-back funding from the Biomedical Advanced Research and Development Authority (BARDA). Also, a US Army licensing arrangement with Sanofi ran into tough political headwinds, with some politicians urging the government to secure an agreement to limit the resulting vaccine's price.
About 20 Zika vaccines are at various developmental stages.
Inactivated vaccine results
The trial of the inactivated vaccine (ZPIV), developed by scientists at the Walter Reed Army Institute of Research (WRAIR), took place at three US sites and involved 67 adults, including 55 who received the aluminum salt–adjuvanted vaccine and 12 who got placebo. Participants received two intramuscular injections of the same dose 4 weeks apart.
More than 90% of those who received the inactivated vaccine had detectable antibodies to Zika virus within 4 weeks of the last dose.
Though the antibody concentration that is needed to protect babies from congenital Zika infection hasn't been determined, the researchers showed that antibodies in the blood of participants who received the vaccine provided robust protection to mice that were experimentally infected with Zika virus.
Anthony Fauci, MD, NIAID director, said in a press release that a Zika vaccine is urgently needed to protect babies from related birth defects and adults and children from other health problems related to the virus. "We are encouraged by initial clinical trial results that indicate the ZPIV vaccine is safe and immunogenic, data that support additional clinical testing of the vaccine to determine its ability to prevent Zika virus infection," he said.
Col Nelson Michael, MD, PhD, who leads the Zika program at WRAIR, said in the NIAID release, "Zika remains a threat to U.S. military personnel and families of service members. We aim to develop a vaccine to protect the military, as well as the global community."
The next research steps for the WRAIR vaccine are to evaluate dosing, scheduling, and prior immunity. To examine how pre-existing immunity might affect vaccine response, WRAIR is vaccinating participants with yellow fever or Japanese encephalitis vaccine before testing the ZPIV regimen. All three viruses are members of the flavivirus family.
Also, a study is set to take place in Puerto Rico in people who have been exposed to flavivirus naturally, such as via a previous dengue infection. Meanwhile, other US studies will assign participants to receive a high, moderate, or low dose to gauge optimal dosing, and another will test various dosing schedules.
Nelson told Reuters that the Army was exploring licensing the ZPIV vaccine to other companies.
One DNA vaccine outperformed other one
The second study tested two forms of a DNA-based vaccine created by NIAID scientists soon after reports surfaced linking Zika infection during pregnancy to birth defects. The vaccines contain a small circular piece of DNA called a plasmid, in which researchers inserted genes encoding two Zika virus surface proteins.
The team tested two different plasmids: VRC5288 and VRC5283. The trial of the VRC5288 version launched in August 2016 and involved 80 healthy volunteers ages 18 to 35 years old at three US sites. They received either two or three doses at different time intervals of 4 milligrams (mg) by needle and syringe in the arm muscle, all at least 4 weeks apart.
Meanwhile, the trial of the VRC5283 vaccine began in December 2016 at the National Institutes of Health Clinical Center and involved 45 healthy volunteers ages 18 to 50 years old. Each received either two or three 4-mg doses at various time intervals. The researchers also compared two vaccine delivery methods—needle plus syringe or needle-free injector—to see which was most immunogenic. In addition, some participants received the full vaccine dose divided with one injection administered to each arm.
Aside from mild to moderate reactions such as tenderness or redness at the injection site, the vaccine was safe and well tolerated by people in both trials.
Analysis of blood samples obtained 4 weeks after final vaccination found that 60% to 89% of those who received the VRC5288 version had a neutralizing antibody response, which was lower than the 77% to 100% of participants who achieved that response after receiving the VRC5283 vaccine.
In the trial of vaccine containing the VRC5283 plasmid, participants who were immunized with the needle-free injector had the highest neutralizing antibody response levels, and those who got a split dose administered to both arms had a more robust response than those who received the full dose in one arm.
The researchers determined that the VRC5283 vaccine showed the most promise and moved it forward to an international efficacy trial in March 2017, with a goal of enrolling at least 2,490 healthy volunteers in areas with confirmed or potentially active Zika transmission in US states, Puerto Rico, Central America, and South America.
In a separate NIAID press release, Fauci said promising phase 1 results support phase 2 testing. According to the NIAID, the goals of the study are also to further evaluate its safety and immunogenicity and determine if it can prevent Zika infection.
Key unanswered questions
In a Lancet commentary on both studies, two experts with the Center for Vaccine Research at the University of Pittsburgh, one of whom is also with Brazil's Fiocruz Institute, wrote that having multiple promising vaccine candidates within 2 years of identifying the link between Zika and microcephaly is impressive.
They wrote said the results from both trials are promising, but more research is needed to address key questions. One is whether viral antigens in the vaccine might cross-react with host molecules. "Full understanding of the mechanism of Guillain-Barre syndrome associated with Zika virus could be crucial to ensure vaccine safety," they added.
Also, they raised concerns about the possibility of whether immunity to Zika from vaccination may alter the behavior of other flaviviruses, such as dengue viruses or dengue vaccination, which could have a clinical impact.
Other challenges are field efficacy testing, given Zika's pattern of rapidly emerging bursts followed by rapid decline, and the difficulty of conducting trials in nonpregnant participants with a disease that has mild symptoms.
"A rapid and accurate assessment of Zika vaccine efficacy is likely to need understanding of overall correlates of protection and mechanisms involved in fetal infection," the two wrote. They noted that it took nearly 30 years for a rubella vaccine to become available, and though Zika incidence has dropped in most countries, its spread has been wide and unpredictable.
"A vaccine to protect against Zika congenital syndrome is still urgently needed," they conclude.
See also:
Dec 4 Lancet inactivated Zika vaccine study
Dec 4 NIAID press release on inactivated Zika vaccine trial
Dec 4 Reuters story
Dec 4 Lancet DNA Zika vaccine study
Dec 4 NIAID press release on DNA vaccine trials
Dec 4 Lancet commentary
