AT DPSG-NA 2017
WASHINGTON (FRONTLINE MEDICAL NEWS) – A DNA vaccine developed at the National Institute of Allergy and Infectious Diseases Vaccine Research Center – one of five National Institutes of Health Zika vaccine candidates – has entered phase 2 testing in a trial underway in Brazil, Peru, Ecuador, Mexico, and Texas.
“The DNA vaccine is a simple 21st century way of developing vaccines that I think will become one of the major [methods of the future] for emerging infections, as opposed to growing a virus and inactivating or attenuating it,” Anthony S. Fauci, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America. With Zika “this is the vaccine that is ahead of all the others.”
The method involves the insertion into a plasmid of a gene that encodes the virus’s surface protein(s) against which an immune response is sought. When the DNA containing the virus’s gene is injected into an individual, the body’s cells produce viruslike particles and a subsequent immune response. Since the method was employed during the SARS epidemic of 2003, the time from sequence selection to a phase 1 trial has gone from 20 months to 3.25 months (for the Zika DNA vaccine).
Will it be possible to test efficacy, given the declining prevalence of Zika across the Americas, and will it be too late to prevent more disease? Dr. Fauci , director of NIAID, said that’s a concern, and that an accelerated approval based on a bridging of animal efficacy data with human safety and immunogenicity data might be possible.
The Southern hemisphere is “entering their summer, so it’s conceivable there will be an uptick in Zika. … We’ll just need to wait and see,” he said.
The Zika virus is part of a “long line of arboviruses that have threatened us in the Americas,” but infection with the organism is “the first – and may be the only – arthropod-borne or mosquito-borne infection that is also sexually transmitted,” Dr. Fauci said.
Sexual contact as an important mode of viral transmission “has been documented very clearly through a number of studies in which individuals clearly had no exposure to mosquitoes but were in fact a sexual partner of someone who got infected,” he said. And recent research suggests that the “female reproductive tract is a preferentially permissive site for Zika replication, which adds to the concern about sexual transmission.”
He cited a study published in July 2017 in PLOS Pathogens in which the Zika virus was found to preferentially replicate in the reproductive tract of female rhesus macaques who received vaginal inoculations of the virus.
Zika virus was “detected in the reproductive tract before it was detected in plasma, and replication levels in the reproductive tract did not reflect viral levels in other parts of the body,” according to the author summary. The kinetics of virus replication and dissemination after intravaginal inoculation were markedly different from what was previously seen in macaques infected with the Zika virus by subcutaneous infection, the report noted ( PLOS Pathogens 13:e1006537 ).
Dr. Fauci briefly described this and several other studies and findings that he said exemplify growing knowledge of the infection. He pointed to a prospective observational study that documents episodes of oligospermia in 15 men who presented with infection in 2016 in the French Caribbean ( Lancet Infect Dis. 2017;17:1200-08 ).
Sperm counts fell in some of the study participants by about 50% between days 7 and 60 post infection, and the counts “recovered somewhat” by day 120. “We’re still following patients in prospective studies to determine if there’s a long-term effect in men,” he said.
In the meantime, he said, research in mice has shown that “without a doubt, Zika infection damages the testes,” Dr. Fauci said, noting that the mouse model is proving to be a good model for studying Zika’s effects. “They become oligospermic and have testicular atrophy.”
Regarding maternal-fetal transmission, there’s evidence that placental trophoblasts “are exquisitely permissive for Zika virus replication,” he said.
In another recent study, primary human placental trophoblasts from nonexposed donors were found to be infected by the Zika virus ex-vivo and permissive for viral RNA replication, compared with dengue virus, a fellow flavivirus (Sci Rep. 2017;7:41389. doi: 10.1038/srep41389 ).
However, Yoel Sadovsky, MD, who also presented at the meeting, explained that his lab’s ex-vivo studies show that primary human trophoblasts have inherent resistance to a number of viruses – and that trophoblasts are refractory to direct infection with the Zika virus. “We don’t think the trophoblasts are very permissive at all,” he said.
Moreover, trophoblasts appear to confer their antiviral effects to other nontrophoblast cells by releasing a particular type of interferon – type III interferon IFN1 – and by delivering certain micro-RNAs (C19MC miRNAs) that are packaged within trophoblast-derived nanovesicles called exosomes, said Dr. Sadovsky , scientific director of the Magee-Womens Research Institute and professor of ob.gyn., reproductive sciences, microbiology, and molecular genetics at the University of Pittsburgh.