The Threat of the Zika Virus and Development of a Vaccine via the use of “Challenge” Clinical Trials

The now well-known, feared mosquito-borne Zika virus, is generally propagated by multiple person bites by a mosquito that is indigenous to tropical and subtropical climates. Zika has also recently entered the United States, with travel-related infections noted in all 50 states, and person-to-person transmission in Florida and Puerto Rico.(1) Consequently, mosquito control and containment measures are intensively underway.
Zika virus transmission routes
While predominantly transmitted from person-to-person by bites from its mosquito carrier, Zika can be also transmitted by sexual relations; this mode has been confirmed in southern Florida, Puerto Rico, Virgin Islands, and the American Samoa.(1) (Figure 1). While recipients of the Zika virus typically exhibit only mild symptoms, the infection is particularly dangerous to pregnant women, often resulting in infant microcephaly (i.e., smaller than normal heads/brains, Figure 2)), associated with several birth defects, eye defects, hearing loss, and impaired growth.(2) In the U.S., of 953 pregnant women infected with Zika, 28 liveborn or infantile-mortal infant, with birth defects, have been confirmed.(1) One group has now shown one Zika strain that infects “stem cells” that develop into the nervous system, in human fetuses.(3)
microcephaly symptoms
While Zika was first discovered in Uganda in 1947, outbreaks remained largely localized, and its complications were unknown. However, its outbreak in the French Polynesia (southern Pacific), in 2014, was followed by rapid spread through Brazil, into Central America and the Caribbean islands into the southeast U.S. (Figure 3).(4) It is possible that the virus has mutated to become more virulent and/or transmissible, but this possibility remains unknown.(5)

In addition to the above mentioned pregnancy complications, Zika was also found to damage mouse testes, and by infection of sperm, is transmissible sexually. By damaging sperm cell precursors, the virus can also lead to male mouse infertility.(6) It is yet to be determined whether this phenomenon occurs in male humans.

Last summer (2016), researchers at Johns Hopkins University began a Zika vaccine clinical trial enrolling participants in a clinical trial to facilitate development of a vaccine against Zika. One notable aspect is that this study represents a “challenge trial,” involving the injection of live vaccine into experimentally vaccinated human volunteers six months prior. While this and similar trials have received approval by regulatory bodies, some debate remains about the assurance of “minimizing risk” to volunteer enrollees.(7) It also remains uncertain whether women volunteers can later safely undergo pregnancy without harm to the fetus. Nonetheless, this type of clinical trial remains the most efficient method of vaccine development.(8,9)

While clinical trials will not likely begin before January 2017, a large group of collaborators has identified several existing FDA-approved compounds that inhibit virus growth, while protecting neuronal cells; these compounds included niclosamide (an anti-malaria drug) and ten other (structurally dissimilar) drugs.(10) Since these compounds are already FDA-approved for other conditions, they can be studied as “off-label” drugs in humans, although the cost of such drug uses may not be reimbursable.(11) Should these demonstrate efficacy in infected persons, combined with mosquito control effects, Zika should be amenable to confinement. Nonetheless, due to lack of knowledge of maternal or sexual transmission, suspected patients should work closely with their doctors, and authorities must continue to intensely monitor disease geography.


  1. Centers for Disease Control, 2016, updated).
  2. Brasil P, Pereira JP, Jr., Raja Gabaglia C, Damasceno L, et al., Zika Virus Infection in Pregnant Women in Rio de Janeiro – Preliminary Report.N Engl J Med. 2016;
  3. Tang H, Hammack C, Ogden SC, Wen Z, et al., Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth.Cell Stem Cell. 2016;18:587-90.
  4. Vox media. Obama has a new plan to fight Zika, asks Congress for $1.8 billion (2016)
  5. Pettersson JH, Eldholm V, Seligman SJ, Lundkvist A, et al., How Did Zika Virus Emerge in the Pacific Islands and Latin America? MBio. 2016;7
  6. Govero J, Esakky P, Scheaffer SM, Fernandez E, et al., Zika virus infection damages the testes in mice.Nature. 2016;
  7. Weijer C, Grimshaw JM, Taljaard M, Binik A, et al., Ethical issues posed by cluster randomized trials in health research.Trials. 2011;12:100.
  8. Atmar RL, Bernstein DI, Harro CD, Al-Ibrahim MS, et al., Norovirus vaccine against experimental human Norwalk Virus illness.N Engl J Med. 2011;365:2178-87.
  9. Sauerwein RW, Roestenberg M, and Moorthy VS, Experimental human challenge infections can accelerate clinical malaria vaccine development.Nat Rev Immunol. 2011;11:57-64.
  10. Xu M, Lee EM, Wen Z, Cheng Y, et al., Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.Nat Med. 2016;22:1101-7.
  11. American Society of Clinical O, Reimbursement for cancer treatment: coverage of off-label drug indications.J Clin Oncol. 2006;24:3206-8.

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