Two Anti-Ebola Vaccines in Historic Race

One of history's most fast-tracked vaccines--an Ebola “ChAd3” vaccine—just entered clinical trial in humans. It may wrap in November. Five weeks of protection in macaques leapt to 10 months after a booster was given two months out. It was the first demonstration of durable immunity against Ebola.

There are problems. Five weeks isn’t long. Boosters are impractical, as re-finding patients in the field can be a nightmare. And durable immunity with that vaccine has only been shown against a mild lab form of Ebola—not the harsher African Ebola.

But a second fast-tracked anti-Ebola vaccine—called an “rVSV” vaccine—is hot on its heels, entering trial at month’s end. That vaccine may be more effective, proponents say. One shot may offer a year of protection.

There is a problem there, too: it’s not as far along. Much published evidence exists of its short-term--not yet its durable--immunity. A paper this year found an rVSV vaccine provided an impressive 14 months of durable immunity. But that was in monkeys with Marburg, not Ebola— a virus close to Ebola, not identical. (Marburg may be less virulent.) By contrast, the durable-immunity ChAd3 vaccine study was published in Nature Medicine Sunday.

Still, ithere is enough similarity that the Marburg data have excited Ebola researchers, said rVSV vaccine co-developer Thomas Geisbert of the University of Texas Medical Branch in an interview. And data presented to conferences show a similar rVSV vaccine—from Profectus Biosciences—protected non-human primates from Ebola for at least 28 days, Geisbert said. Finally, as the rVSV vaccine is replication-competent, Geisbert thinks it will prove more durable than the ChAd3 vaccine “by a landslide.”

But the main reason these two vaccines are fast-tracking is Ebola itself. A World Health Organization (WHO) meeting of 200 top virologists decided last week to rush both vaccines, as the accelerating Ebola epidemic has taken more than 2,000 lives—most in recent weeks.

“This is absolutely unprecedented,” Marie-Paule Kieny, WHO assistant director-general, told reporters after the summit. “We must move as fast as possible.”

The chimpanzee cold vaccine 

The first vaccine out of the gates, as noted, is a chimpanzee-derived replication defective adenovirus (ChAd3) vaccine being shepherded to clinical trial, as of last week, by GlaxoSmith Kline and the National Institute of Allergies and Infectious Diseases (NIAID). It is a disabled “chimp cold” virus genetically engineered to contain both Ebola and Marburg viral DNA. 

That disabled virus slips into healthy cells as normal cold viruses do, and co-opts the cell’s machinery, causing it to pump out minute levels of Ebola protein. As levels are so low, the healthy body has time to create an immune response to the virus—then, and later.

In Sunday's Nature Medicine paper, a team led by NIAID’s Nancy Sullivan found the vaccine protected four of four monkeys from Ebola for five weeks. A “boost” of a second vaccine made with (a modified ankara virus (MVA)) resulted in full protection for ten months (as half of all monkeys died at ten months on a single ChAd3 vaccine injection). 

The Sullivan team vaccine entered clinical trial in healthy people last week—sans boost. The trial may end in November, and go to Africa soon after. (There is no timetable for the boost.)

“We have demonstrated, for the first time, to our knowledge, that both acute and durable immunity against EBOV [Ebola] can be achieved using a single inoculation (partial protection) or a prime-boost regimen (uniform protection),” Sullivan’s team said in the paper.

Livestock (‘VSV’) vaccine may be stronger

The second anti-Ebola vaccine that NIAID will help enter trial this month may provide longer protection in a single shot, its proponents say.

Made of a recombinant Vesicular Stomatitis livestock Virus (rVSV), that Ebola vaccine is being tested by New Link Genetics Corp., which licensed it from the Public Health Agency of Canada. Its trial will be held at the Clinical Trials Center of Walter Reed Army Institute of Research.

University of Manitoba microbiologist Gary Kobinger recently found that rVSV vaccine protected 12 of 15 rodents against Ebola— the virulent (“7A”) kind found in Africa— for one year, and offered complete protection at nine months. That vaccine was originally developed ten years ago by Heinz Feldmann, then with the Public Health Agency of Canada and Geisbert. It is very similar to the next-gen rVSV vaccine Geisbert is testing at Profectus. 

As noted, a Geisbert paper this year found all monkeys receiving a similar next-gen rVSV vaccine were fully protected for 14 months when challenged with the similar Marburg.

And in unpublished work presented at conferences, the next-gen anti-Ebola rVSV vaccine fully protected three of three monkeys against a wild-type strain of Ebola Zaire (the “7A virus”), Profectus CSO John Eldridge said by email. “Three macaques received a single IM injection of the Profectus rVSVN4CT1 vectored Ebola-Zaire vaccine, and two were naïve controls.  All were challenged with 1,000 PFU highly virulent low passage 7A Ebola virus 28 days after the single vaccination.  All three vaccine recipients were completely protected against any disease, while the naïve controls died of fulminant Ebola hemorrhagic fever."

Meanwhile, the ChAd3 vaccine was only tried on the weaker, lab-derived 8A version of Ebola In the Nature Medicine work. “With a challenge virus (8A) that is less virulent due to passaging in vitro, it is like challenging with a lower dose (less than half),” said Kobinger. “These conditions would not necessarily translate into complete protection with the more virulent 7A isolate…From the human data I have seen from patients treated with ZMapp, the non-human primate model with the 7A virus is pretty close to what is seen in humans with the currently circulating Zaire in West Africa.”

Kobinger, now working on the New Link VSV vaccine, once researched adenoviruses like ChAd3. “I was part of the team that isolated the first simian adenoviruses at U Penn in the early 2000s, working since on different adenoviruses,” he said. “Finally I decided this year it was enough. Why try to always be as good as VSV when you can just use VSV?” 

The bottom line: “I would prefer being vaccinated with a vaccine that protects against the 7A and sets the bar high. ‘Long term’ in the [Nature Medicine] paper is not really long-term for a vaccine. What would happen after two years is anybody's guess. The higher the bar the more likely it will really be long term--years not months.”

Debate over the published ChAd3 vaccine

ChAd3 proponents say there is not enough published work on 7A and 8A differences to draw conclusions. But Geisbert, too, wishes the ChAd3 vaccine was tried against the more virulent 7A Ebola, as the rVSV vaccines were in his above-mentioned unpublished Ebola study in monkeys, and in Kobinger’s mouse study. “This is a huge issue,” he contended. “We know USAMRIID has used a laboratory-adapted variant of Ebola-Zaire virus with a predominance of 8U residues at the GP editing site (see this PLOS One paper for explanation of how viruses from patients change when passed in culture). I have done [unpublished] studies where animals given vaccines including the Ad5-based vaccine previously shown to provide complete protection of monkeys against laboratory adapted ‘8U’ viruses, were unable to provide complete protection against wild type viruses with high populations of the wild type ‘7U’ residues.”

Furthermore, Geisbert says, a study has found VSV vaccines can even fight Ebola after infection. “The VSV-based vaccines can protect monkeys when given shortly after exposure (50 to 100 percent, depending on the filovirus).”

Geisbert believes “single injection protection is very important in the context of responding to an outbreak. The prime boost [ChAd3] data is interesting, and they make a point about still having protection at 10 months. But in the context of an outbreak you would not have time to prime and boost.”

He also finds that Ebola vaccines made with MVA, like the ChAd3 vaccine boost, can have side effects. ChAd3 proponents say this has not yet been seen.

Finally, while there have been concerns about neurological side effects of rVSV vaccines, Geisbert found in 2012 no neurological problems in 14 of 14 monkeys given a VSV Ebola vaccine.

Already building up doses

Regardless, the ball is rolling. Canada will donate 800 to 1,000 doses of the New Link rVSV vaccine, and Kobinger says between 1,500 and 15,000 doses of it are being made bi-monthly.

The WHO says some 15,000 doses of the ChAd3 vaccine may be ready by year’s end.

Other vaccines

The Profectus rVSV vaccine should enter clinical trial in ten months. An adenovirus vaccine is being developed by Johnson & Johnson.