Ebolavirus vaccines and antivirals

8 August 2014

guinea-liberia-sierra-leone-2014As the epidemic of Zaire ebolavirus in Western Africa continues (1,779 cases and 961 deaths in four countries), many are questioning why there are no means of preventing or stopping infection. In the past two decades there has been substantial research into developing and testing active and passive vaccines and antiviral drugs, although none have yet been licensed for use in humans.

Using antibodies to treat infection with ebolaviruses with antibodies is probably the best known therapy, because it was used to treat a two Americans who were infected while working in Liberia. They received a mixture of three monoclonal antibodies (called ZMapp) which had been previously shown to block infection of cells with ebolaviruses, and prevent lethal infection of non-human primates when given within 24-48 hours after infection. These are mouse monoclonal antibodies that have been ‘humanized’ so that when given to people they do not induce an antibody response against the antibodies. Humanization involves changing the amino acids of the antibody molecule from mouse to human, except in the part of the antibody that binds antigen. The antibodies are then synthesized in tobacco plants and purified. Administering anti-viral antibodies to patients, also called passive immunization, was done long before vaccines were available. Serum from patients who had recovered from a particular disease would be given to others who had recently been infected, in order to prevent disease. Such therapy was used to save the life of virologist Jordi Casals, who had become infected with Lassa virus while isolating the virus from the blood of a patient, Penny Pinneo. The serum administered to Casals was obtained from Pinneo, who had recovered from the infection. The American doctor infected with Zaire ebolavirus while working in Liberia was also given serum from a boy who had recovered from infection.

As ZMapp has not yet been subjected to human clinical trials to determine its safety and efficacy, its use in an infected human is considered unusual. A phase I clinical trial needs to be done to ensure that the preparation of monoclonal antibodies is safe in humans. Determining whether monoclonal antibody therapy for ebolavirus infection is effective is more difficult. Such testing could only be done during an outbreak, during which it would not be ethical to withhold treatment from the control group. Nevertheless it is clear that such mixtures of monoclonal anti-viral antibodies could potentially save many lives during outbreaks.

While passive immunization has value in saving lives, its protection is temporary: the antibodies given to patients do not endure. A better approach is immunization, which not only induces anti-viral antibodies, but creates immune memory, so that subsequent infections are accompanied by another round of antibody production. The catch is that it takes about two weeks after immunization for antibodies to reach sufficient protective levels. Nevertheless, a vaccine would likely have had substantial impact on the current outbreak, which began in March 2014 and has continued for 5 months.

A number of experimental vaccines against ebolaviruses are in development. In one approach, the glycoprotein of vesicular stomatitis virus is replaced with the corresponding protein of different ebolaviruses. These vaccines protect non-human primates from lethal infection. A similar approach using an attenuated rabies virus to deliver the ebolavirus glycoprotein also protected non-human primates from infection, as did immunization with an adenovirus encoding the ebolavirus glycoprotein.  This vaccine candidate has been shown to be safe and immunogenic in phase I clinical trials. Another vaccine approach entails production of the ebolavirus glycoprotein in E. coli. Immunization of mice with the purified protein leads to the production of neutralizing antibodies. Because protein-based vaccines do not replicate, the immune response may need to be boosted by using an adjuvant that stimulates the innate immune system and leads to better antibody production. A double-stranded RNA adjuvant has been shown to augment the immune response against a non-infections, virus-like particle vaccine containing the Ebola virus glycoprotein but not the viral genome.

Antivirals certainly have a place in control of viral disease, and a number of promising candidates to control infection with ebolaviruses have been developed. One is a nucleoside analog which is incorporated into RNA by the viral RNA polymerase and leads to chain termination. It blocks replication of ebolaviruses in culture cells, and protects mice and nonhuman primates from lethal infection. This compound, called BCX4430, is a broad spectrum antiviral that inhibits the replication of not only members of the Filoviridae, but also Arenaviridae, Bunyaviridae, Orthomyxoviridae, Picornaviridae, Paramyxoviridae, Flaviviridae, Coronaviridae. Another inhibitor of viral RNA synthesis is favipiravir, which has the advantage of being in late stage clinical development for the treatment of influenza. This compound inhibits replication of ebolaviruses in cultured cells and reduces disease severity and mortality in a mouse model of disease.

It is likely that the extent of the current outbreak of Ebola virus disease, the largest to date, will provide impetus to move some of these treatments into human trials. But consider that all the research on active and passive vaccines and antivirals for ebolaviruses required work in BSL-4 laboratories. Those who call for the shuttering of BSl-4 laboratories need to take note and move away from their unrealistic and unreasonable position.

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  • Torsten Wurm

    I hope that the outbreak will increase funding not only for research but also funding to train more local healthcare workers and to improve the healthcare system in West Africa. Yes we need antivirals and a vaccine, but we also need an infrastructure which allows to administer them and to treat those who are infected. Unfortunate for clinical trials the disease does not surface very often – fortunate for the people, but difficult for clinical trials. Animal studies can only mimic these trials. So what to do? Get the safety done especially for antivirals so those are available. Antivirals which are already available or in the pipeline for treating other viral infections should be tested in EBOV infected animals. Train local healthcare workers locally which can build am atmosphere of trust. The real heroes in this outbreak who died were local healthcare workers. Kudos to them.

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  • mbarnkob

    Thanks for an very interesting post. One thing I wondered concerning Zmapp is if the antibodies can reach all vira in the body – if not, wouldn’t this only be a temporary solution, as the virus could then reignite, once the antibody is no longer being administered and has been cleared?

  • hholme

    Re TWiV 297: Ebola! Don’t panic. AUGUST 10, 2014

    I thought the approach taken was incorrect. Too much of the time, you seemed to be
    assuming that only rich Westerners, behind secure borders, with top flight
    hospitals, with many thousands of dollars per infected person (payable by rich governments with national health services), were the appropriate subjects of the podcast. You did not adequately discuss how to stop the spread of Ebola virus in Africa, the second largest and second most populous continent, with more than 1 billion people. While I may not panic, what should the millions of people of West Africa do?

    Four days after your August 10 podcast, the World Health Organization said “Staff at the outbreak sites see evidence that the numbers of reported cases and deaths
    vastly underestimate the magnitude of the outbreak. . . . These steps align with
    recognition of the extraordinary measures needed, on a massive scale, to
    contain the outbreak in settings characterized by extreme poverty,
    dysfunctional health systems, a severe shortage of doctors, and rampant fear.”

    August 28, WHO issued its Ebola Response Roadmap , http://apps.who.int/iris/bitstream/10665/131596/1/EbolaResponseRoadmap.pdf?ua=1, and said: “As of 27 August 2014, the cumulative number of Ebola cases in the
    affected countries stands at more than 3000, with over 1400 deaths, making this
    the largest Ebola outbreak ever recorded, despite significant gaps in reporting
    in some intense transmission areas. . . .

    “This Roadmap assumes that in many areas of intense transmission the actual number of cases may be 2-4 fold higher than that currently reported. It acknowledges that the aggregate case load of [Ebola Virus Disease] could exceed 20,000 over the course of this emergency. The Roadmap assumes that a rapid escalation of the complementary strategies in intense transmission, resource-constrained areas will allow the comprehensive application of more standard containment strategies
    within 3 months. This plan
    recognizes that a number of currently unaffected countries could be exposed to
    EVD, but assumes that the emergency application of the standard control strategies will stop any new transmission within 8 weeks of the index case.”

    I suggest you agree the Roadmap assumptions are unrealistic, even with 20,000 cases.
    Why should the actual number of now cases be only 2-4 fold higher than
    the numbers “reported by the respective Ministries of Health of Guinea, Liberia, Nigeria, and Sierra Leone [at] 3069, with 1552 deaths”? Very large areas are under military, and poorly, enforced quarantine, including the Monrovia West Point slum of perhaps 100,000, in the capital city of 1 million.

    Why should “standard containment” (i.e. the kind of containment you might expect in the US) exist within 3 months? What chances do you give that any new transmission will end within 3 months plus 8 weeks?

    You discussed how if this virus was transmissible as airborne aerosol, and I paraphrase, all bets would be off. A paper was published in Science, August 29, 2014. http://www.sciencemag.org/content/early/2014/08/27/science.1259657.full

    “Five of the paper’s more than 50 co-authors died from Ebola before publication. . .We’ve uncovered more than 300 genetic clues about what sets this outbreak apart from previous outbreaks,” said Stephen Gire, one of the study’s co-authors and an infectious disease researcher at Harvard.”

    How do you know that mosquitoes will not puncture some of the horrifying
    Ebola pustules and begin spreading the disease? http://insidesurgery.com/2014/07/rife-treatment-stop-ebola-disease/ebola-hand1/

    How do you know that some of the inadequate number of needles that someone might use repeatedly, after inadequate sterilization, to try to rehydrate Ebola patients, won’t spread the infection? How do you know that the WHO allowance of continued international flights will not spread the disease? How do you know that boatloads of Ebola refugees will not spread the disease to many countries?

    I’ll send Vincent something I suggest he read in penance for ignoring a realistic discussion of present and future very large suffering and death from Ebola, and how to stop it. See Jean Raspail’s, The Camp of the Saints. http://www.amazon.com/The-Camp-Saints-Jean-Raspail/dp/1881780074

    This apocalyptic fiction published in 1973, envisions hundreds of thousands of sick and desperate refugees landing in a western country at once.

  • Kevin Worldsavior

    I got the Ebola virus devastating destroyer by which the virus is killed the moment it touches us – its protein decoy cannot save it from being destroyed instantly – I can eliminate the Ebola crisis for just a few days – Once I am paid the corresponding funds for that.

  • https://www.facebook.com/TheGamingAlcoholic The Gaming Alcoholic

    Once you are paid the corresponding funds…

    So in other words, never.

    Keep trying scumbag.

  • Eric McMahan

    If someone is infected with ebola reston virus, which doesn’t appear to be lethal to humans, will they develop antibodies that will protect them from the other strains of ebola?

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