It sounds counterintuitive, but one of the main arguments for getting a Zika virus vaccine into human trials is that as susceptible people become immune through prior infection, it will be harder to test vaccine efficacy in a large population.
Though there is less immediate need for a vaccine if the Zika virus fades back, the problem is that no vaccine will be available if it returns later to infect susceptible populations. This very point was made during the massive Ebola epidemic outbreak in West Africa, where no vaccine was available because it was not developed during past outbreaks of the hemorrhagic virus.
One caveat that bears mentioning at this juncture: The CDC is urging vigilance and warning that Zika will return as the weather warms and Aedes egypti mosquitoes that carry the virus emerge across a large swath of the nation.
An ethics panel recently advised federal public health officials against using controlled human infection trials to test Zika vaccines, but said the model may be justified if the virus begins to wane. A researcher who developed a controlled human infection model for dengue virus — which is closely related to Zika — questioned the panel’s decision to red-light the approach, warning that this may end up being a missed opportunity.
IRB Advisor asked Anna P. Durbin, MD, a professor and researcher in the Johns Hopkins University Vaccine Initiative, to discuss this point and explain how Zika vaccine controlled human infection trials could proceed safely.
IRB Advisor: Are you concerned that Zika virus will diminish to the point that wouldn’t be able to test a vaccine in a large population?
Durbin: I am absolutely concerned about that. If you look at the data right now, this is the peak season for Zika in South America, but they are seeing very few cases. In Puerto Rico and the Caribbean we may see some more cases this summer, but I’m not convinced there will be enough Zika circulating by the time a vaccine is ready to go into Phase III trials for efficacy studies. It may become very sporadic like chikungunya virus or West Nile, and it will be difficult to predict where it is circulating. You want to have a vaccine ready to go in case it comes back. It needs a susceptible population, and as it went through Brazil and South America, those countries have fewer and fewer susceptible people. So then you have to wait until there are new birth cohorts that are susceptible.
IRB Advisor: The Zika vaccine ethics panel report cited the risk of transmission from study participants to their contacts. What assurances to you have that this would not occur?
Durbin: When you look at the data, third-party transmission or sexual transmission is not common. More than 40,000 travel-associated cases of Zika have resulted in some 40 cases of sexual transmission, which is less than 1%. The big problem is that we don’t have very good data on shedding of actual virus that we can replicate. Everything is done by PCR, which doesn’t tell you whether that virus is infectious — it only tells you that pieces of that virus were recovered.
IRB Advisor: What are the advantages to using human infection vaccine challenges?
Durbin: The reason we think controlled human infection trials are valuable is you can have a very early look at whether or not your vaccine may be protective. With Zika, I think we have a higher bar than we have had with any other vaccine. Because we know from the epidemiological studies that have been done that infection at any time during pregnancy carries a risk. We know that asymptomatic women have given birth to babies with microcephaly or Zika congenital syndrome. You don’t have to be symptomatic with Zika in order to transmit the virus to the fetus. So that makes us think that even small amounts of virus could be transmitted to the fetus and result in congenital Zika syndrome.
IRB Advisor: So that increases the difficulty of developing a vaccine?
Durbin: As a vaccine developer, that tells us that we need a very high bar of protection. We need to try to prevent any Zika virus from infection to the mother. When we look at most vaccines, we are looking to not necessarily prevent infection because that is a very high bar, but you want to see aggregation of disease. People may become infected but they don’t get sick. We don’t think that is going to be enough with Zika. You may have to actually prevent infection, and you cannot study that in traditional efficacy studies because you won’t pick up asymptomatic infections in Phase II or Phase III trials.
IRB Advisor: But you may be able to overcome these issues with a human infection protocol?
Durbin: You can use a controlled human infection model, where you vaccinate people [with a Zika candidate vaccine] and then at some time point later — whether it is a month or six months, 12 months — you administer a known amount [of virus] by subcutaneous injection. We know exactly how much they received. We administer it like we would any drug, drawing it up in a syringe and then injecting it under the skin. Then we would follow [research subjects] very closely in inpatient settings for about two weeks. We would sample blood and probably urine, saliva, semen, and vaginal secretions for women to see if we can recover any virus. If we recover virus, we would sample using both PCR and old-fashioned virology tissue culture to see if that virus is replicating or not. If it is and you recover virus, then you know that your vaccine did not induce sterilizing immunity. Then you would have to decide whether it is worth using that vaccine.
IRB Advisor: Would you use some kind of attenuated or weakened Zika strain to induce the controlled human infection?
Durbin: When we think about what would be a good Zika immune challenge, the first thing we want is an isolate from someone who had uncomplicated Zika — so either a very mild illness or no discernable illness. And then we would start with administering a very low dose. So for the dengue model we found that 100% of research subjects had replicating virus, but the virus is at a low titer. It is 2.5 logs, about 300-400 virus particles [per ml]. Whereas when people are sick with dengue that have 10,000, 100,000, 1 million virus particles per ml. So we’re 100- to 1,000-fold below the level that would make people sick.
IRB Advisor: So if you challenge vaccine immunity with low titers of Zika, that would be unlikely to transmit from the recipients to others?
Durbin: That is exactly our intent. We don’t want transmission and we reduce the risk of that by giving a dose that low levels of viremia in the recipients and that’s what we have been able to do with the dengue controlled human infection model. It doesn’t replicate to high enough titers to be transmitted by mosquitoes.
