Battling Ebola: The Virus and the Fear

Recent estimates put the total number of Ebola deaths at close to 6,000, which means it will leave more dead than all other outbreaks of the virus combined. The majority of these deaths occurred in the West African countries of Liberia, Sierra Leone, and Guinea.

Only two people died from Ebola in the US after contracting the disease in West Africa, yet the threat of the virus seemed to dominate news coverage here over the past few months. During this time it was Anthony Fauci, the long-time, unflappable head of the US National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH), who spoke out in an effort to stoke Ebola fears and explain current efforts to develop a vaccine that could prevent future outbreaks like this one. As is often the case, Fauci was a voice of reason, and he is extremely confident a vaccine against this terrible disease will be a reality.

NIAID, which Fauci has led since 1984, and other groups at the NIH are involved in developing and testing some of the leading Ebola vaccine candidates, as well as conducting a portfolio of research activities on AIDS vaccines.

Fauci needs no introduction to anyone familiar with HIV/AIDS. He’s remained at the forefront of the pandemic since the earliest days, as a physician, scientist, and administrator. He became an ally of AIDS activists fighting for treatment and is one of the most vocal proponents for AIDS vaccine and cure research. He oversaw a budget of US$4.5 billion at NIAID last year.

In November, just after the close of the HIV R4P conference in Cape Town at which his talk was delivered by video due to his need to remain in the US to deal with the Ebola response, IAVI Report Contributing Editor Kristen Jill Kresge spoke with Fauci about the similarities and differences between Ebola and HIV and the efforts to develop vaccines to target both of these deadly diseases.

Following our talk, researchers from the Vaccine Research Center at NIAID and their colleagues published the first data from a Phase I study of an Ebola vaccine in human volunteers (NEJM doi:10.1056/NEJMMoa1410863). This trial showed that a replication-defective chimpanzee adenovirus serotype-3 vectored vaccine candidate encoding two Ebola proteins isolated from previous outbreaks in Zaire and Sudan was safe at both doses tested and induced Ebola glycoprotein-specific antibodies in all 20 volunteers. Those who received the highest dose developed a transient fever following vaccination, but also had higher antibody titers and were more likely to have CD4+ and CD8+ T-cell responses than volunteers who received the lower dose. It remains to be seen if these immune responses will be sufficient to actually protect against Ebola infection. But Fauci said the current outbreak provides an unexpected opportunity to study the efficacy of these vaccine candidates in Liberian volunteers in efficacy trials that could start as early as this month.

On December 2, US President Barack Obama visited the NIH in Bethesda, Maryland, where he highlighted advances in Ebola vaccine research and congratulated NIH director Francis Collins and Fauci for their work.

In news coverage some public officials, including Thomas Frieden, director of the US Centers for Disease Control and Prevention, drew comparisons between the current Ebola epidemic in West Africa and the early days of HIV. How are these two epidemics similar in your view?

I don’t make any analogy between Ebola and HIV. They are entirely different. The only thing that is possibly similar in an entire arena of dissimilarities is the somewhat understandable, but inappropriate, fear associated with transmission and contracting each of these infections. There was unreasonable fear early on in the AIDS pandemic about how you might get it. There were people talking about getting it from a gay waiter that was waiting on you in a Greenwich Village restaurant, or from a mosquito, or by sitting next to an infected child in school. Those are all fears, understandable as they may be, that were not based on any scientific evidence.

Somewhat similar, is the unrealistic association of what’s going on with Ebola in West Africa and the possibility of there being an outbreak here. People being afraid to get on planes even though there’s no indication at all that anyone who had Ebola was anywhere near the plane.

Those are the only similarities. Once you get beyond that, they are completely different diseases in their mode of transmission and in their impact. Thousands and thousands and thousands of Americans were getting infected with HIV and there wasn’t a lot of attention paid to it in the 1980s. With Ebola, there have been only two infections and both have been in very courageous nurses who have deliberately, of their own volition, put themselves in harm’s way by taking care of an Ebola patient. The amount of fear and sometimes hysteria we see here in the United States about the threat of Ebola is dramatically out of proportion to the risk. With AIDS, people were truly getting infected and the world wasn’t paying attention to it. Here, the United States is intensively focusing on the possibility of Ebola and only two people got infected and we knew exactly how they got infected. They were taking care of a sick person. There are so many differences between these two diseases that I wouldn’t equate them under any circumstances.

Does the fact that there are many people who are cured of Ebola make it more likely that a vaccine will be developed?

That is the most critical point and is why I am extremely confident that we will develop a successful vaccine against Ebola. As I have said many times in my discussions about an HIV vaccine, one of the real scientific obstacles to the development of a successful HIV vaccine is that unlike in classic vaccinology, when you look at the response to natural infection—be it against polio, smallpox, hepatitis, or measles—even though there are degrees of morbidity and mortality associated with those infections, at the end of the day, in most cases the body spontaneously and naturally recovers. And that leaves you with lifelong immunity against a similar strain. So nature has already provided you with a proof of concept in these infections that the body is capable of making an adequate immune response.

We don’t have that with HIV because in an unprecedented way the body does not seem to make an adequate immune response, at least not very often or not very consistently. Whereas with Ebola, given the number of people who recover and have developed an immune response that ultimately protects them in subsequent infections with the same strain, the proof of concept has already been provided. Nature tells us it is quite possible if not highly likely that we will develop a successful vaccine against Ebola.

Which of the Ebola vaccine candidates are furthest along in development?

There are two already in Phase I trials and getting ready to move into more advanced trials. They are the NIH/GlaxoSmithKline vaccine, which is a chimpanzee Adenovirus serotype-3 that has already enrolled all Phase I volunteers, and we are now designing a randomized, controlled trial to be conducted in Liberia to determine efficacy [see page 11 for update].

The other candidate is a vesicular stomatitis virus (VSV) vector vaccine expressing the glycoprotein gene of Ebola and that is in a Phase I clinical trial here at the NIH and at Walter Reed in Silver Springs [Maryland]. Both of those are in the middle of completing Phase I trials.

There are several other vaccine candidates that are not yet at that level but soon will be.

Interestingly, both of those are vectors also being investigated for HIV vaccine research, as well as for other vaccines. Do you think the development of an Ebola vaccine could provide information useful to developing future HIV vaccine candidates?

I think so. I think any time you accumulate knowledge about a particular platform, in this case the adenovirus or VSV vectors, it’s always helpful when you use that same platform for other vaccines for other diseases. That’s exactly what’s going on with Ebola vis a vis HIV. I hope we gain information that is helpful and I think it’s likely that we will.

Has the devastating epidemic that is ongoing in West Africa sparked more interest among the major pharmaceutical companies to develop Ebola vaccines? Were programs sidelined because there wasn’t an urgent need?

We partnered with some companies, such as GlaxoSmithKline, well before the outbreak in West Africa and we were heading toward getting the vaccine approved by the two-animal rule of the FDA [US Food and Drug Administration] because we didn’t anticipate that there would be an outbreak of such a size that you could actually make an attempt to prove efficacy. I think that the lack of an Ebola vaccine up to this point was more related to the lack of industrial partners than the fact that there were not outbreaks. But the fact that there were not major outbreaks may be the reason why industrial partners were not that enthusiastic. So they’re probably indirectly related.

So when might the first Ebola vaccine be ready for efficacy testing?

Probably it would be ready for testing at the end of December or early January. Hopefully by the beginning of next year an Ebola vaccine will be in efficacy trials.

Do you foresee an Ebola vaccine only being used when an outbreak occurs?

Yes. Prior to the West African outbreak there were 24 Ebola outbreaks that occurred over 38 years between 1976 and 2014 and you had a total of about 2,500 cases, so that’s not a reason to trigger massive vaccination. Also, when you make an Ebola vaccine you want to make it strain specific so that it induces optimal specificity.

How would you characterize the US government’s response to the Ebola epidemic?

As a scientist, I’m trying to make sure we focus on the evidence. And the science tells us that we have a major epidemic in West Africa and that we know how to contain it through public health measures—isolation, identification, contact tracing, and protection of healthcare workers, among other things. We know how to do that and if we do it at a level that’s appropriate to the size and level of the epidemic, we will ultimately get it under control in Africa. In the United States, you have an epidemic of fear. We’ve had two cases that were contracted in the United States. Nobody has gotten infected from somebody in the environment. So you have to continually focus on what the science tells us about how it is transmitted, and how it’s not transmitted. I’ve spent a considerable amount of time in the public and the press trying to get that point across.

HIV has proven an intractable target for vaccine researchers. Do you think it is possible to end AIDS without a vaccine?

I think together the combination of non-vaccine prevention modalities with a modestly, or rather moderately—I don’t think modestly is good enough, we will have to do better than the results of the RV144 trial in Thailand—protective vaccine is going to be the answer to putting an end to the AIDS pandemic.

Do you think improvements to the vaccine regimen tested in RV144 could ultimately lead to the first licensable vaccine against HIV?

It’s possible. I think when you have different vectors that might be better, multiple boosts, and when you add another adjuvant to it, you can amplify the breadth, depth, and duration of immune responses induced in the original RV144 trial.

Are you confident that researchers will also be able to identify a strategy for curing HIV? If so, what might it involve?

I certainly think it’s possible, otherwise we wouldn’t be making investments to pursue an HIV cure. I think a cure is going to be very difficult and I think it’s still so much in the discovery phase that it is almost impossible to make any predictions about how we’re going to cure anybody. We still don’t know enough about the nature of the HIV reservoir—its kinetics, distribution in different cell types, its durability. There are so many unanswered questions. We are very early in the quest toward a cure, so there’s not much you can say other than it’s very difficult to predict.