TWiV 375: Zika and you will find

TWiVOn episode #375 of the science show This Week in Virology, the TWiVziks present everything you want to know about Zika virus, including association of infection with microcephaly and Guillain-Barré syndrome, transmission, epidemiology, and much more.

You can find TWiV #375 at microbe.tv/twiv.

TWiV 322: Postcards from the edge of the membrane

On episode #322 of the science show This Week in Virology, the TWiVodes answer listener email about hantaviruses, antivirals, H1N1 vaccine and narcolepsy, credibility of peer review, Bourbon virus, influenza vaccine, careers in virology, and much more.

You can find TWiV #322 at www.microbe.tv/twiv.

Could the Ebola virus epidemic have been prevented?

Ebola is comingThe cover of this week’s issue of Businessweek declares that ‘Ebola is coming’ in letters colored like blood, with the subtitle ‘The US had a chance to stop the virus in its tracks. It missed’. Although the article presents a good analysis of the hurdles in developing antibody therapy for Ebola virus infection, the cover is overstated. Why does Businessweek think that Ebola virus is coming to the US? (there is no mention of this topic in the article). Are we sure that antibody therapy would have stopped the outbreak? (no, as stated in the article).

How the U.S. Screwed Up in the Fight Against Ebola is an analysis of why ZMapp, the cocktail of monoclonal antibodies that block infection with Ebola virus, has not yet been approved for use in humans. ZMapp was given to two American workers who had become infected with the virus while working in Africa. The two workers recovered, but the role of ZMapp in their recovery is unknown – as the authors of the article note. Although ZMapp can prevent lethal infection of nonhuman primates with Ebola virus, it is not known if it would work in humans. Answering that question requires a clinical trial, and the article explores why this phase was not done years ago. Only after the large Ebola virus outbreak in west Africa did the US provide funds to conduct a phase I trial of the drug.

The article discusses how development of ZMapp languished for years, because the US government did not consider the Ebolaviruses to be a pressing problem. In hindsight they were wrong, and now anyone can seem smart by saying we should have pushed development of Ebola virus vaccines and therapeutics.

The real question is whether we will learn from this experience, and be better prepared for the next viral outbreak. Just because infections are rare or geographically localized should not lessen their importance, as these features can change. Knowing the animal source of a viral infection may also lead to developing ways to prevent infections. For example, because people acquire Hendra virus from horses, immunization of these animals should prevent human infections.

What other antiviral vaccines and drugs should we be developing? This question is difficult to answer because we discover new viruses regularly and making therapeutics for all of them is not possible. Testing an antiviral drug or vaccine against rare viruses is difficult because identifying populations that are at risk for infection may be a hit or miss proposition.

Influenza viruses are at the top of the list for vaccine and drug development, because nearly everyone gets infected. Other viruses we should be ready for include SARS and MERS coronaviruses, dengue virus, chikungunya virus, Lassa virus, Nipah and Hendra viruses. I’m sure you can think of other viruses that belong on this list.

Developing antiviral vaccines and drugs is expensive. For some of the viruses on my list (dengue, chikungunya) there are currently large enough markets that permit involvement of for-profit pharmaceutical companies. Development of therapeutics against viruses that cause rare infections must be supported largely by governments.

The US does not spend enough money on basic life sciences research. We do spend a great deal of money on the military. President Obama recently declared Ebola virus to be a top national security priority. Why not view all infectious diseases in this way, to ensure that they receive the funding for research that they deserve?

While the Businessweek cover is misleading, intended to stimulate sales, the article does make us think about the problems we confront when dealing with rare but lethal diseases. No one should conclude that Ebola virus outbreak in Africa could have been prevented, because antiviral therapies have not yet been tested in humans. But we won’t know if we never do the research.

The Berlin patient

HIV binding CD4 and ccrSince the beginning of the AIDS epidemic, an estimated 75 million people have been infected with HIV. Only one person, Timothy Ray Brown, has ever been cured of infection.

Brown was diagnosed with HIV while living in Berlin in 1995, and was treated with anti-retroviral drugs for more than ten years. In 2007 he was diagnosed with acute myeloid leukemia. When the disease did not respond to chemotherapy, Brown underwent stem cell transplantation, which involves treatment with cytotoxic drugs and whole-body irradiation to destroy leukemic and immune cells, followed by administration of donor stem cells to restore the immune system. When his leukemia relapsed, Brown was subjected to a second stem cell transplant.

The entry of HIV-1 into lymphocytes requires two cellular proteins, the receptor CD4, and a co-receptor, either CXCR4 or CCR5. Individuals who carry a mutation in the gene encoding CCR5, called delta 32, are resistant to HIV-1 infection. This information prompted Brown’s Berlin physician to screen 62 individuals to identify a stem cell donor who carried a homozygous CCR5∆32 mutation. Peripheral blood stem cells from the same donor were used for both transplants. 

Despite enduring complications and undergoing two transplants, Brown’s treatment was a success: he was cured both of his leukemia and HIV infection. Even though he had stopped taking antiviral drugs, there was no evidence of the virus in his blood following his treatment, and his immune system gradually recovered. Follow-up studies in 2011, including biopsies from his brain, intestine, and other organs, showed no signs of HIV RNA or DNA, and also provided evidence for the replacement of long-lived host tissue cells with donor-derived cells. Today Brown remains HIV-1 free.

Although Brown’s cure is somewhat of a medical miracle, and by no means a practical road map for treating AIDS, the example of the Berlin patient has galvanized research efforts and continues to inspire hope that a simpler and more general cure for infection may someday be achieved. Clinical trials have been conducted to test a variety of strategies in which CD4+ T or stem cells are obtained from a patient, the CCR5 gene is either mutated or its translation blocked by RNA interference, and then the resulting virus-resistant cells are returned to the patient. In one case zinc finger nucleases were used to delete the CCR5 gene in a patient’s cells, a procedure that we discussed in TWiV #278.

TWiV 298: MV-NIS de myelo

On episode #298 of the science show This Week in Virology, the TWiV gang answers follow-up questions about the Ebola virus outbreak in West Africa, then discuss treatment of  disseminated multiple myeloma with oncolytic measles virus.

You can find TWiV #298 at www.microbe.tv/twiv.

TWiV 297: Ebola! Don’t panic

On episode #297 of the science show This Week in Virology, the TWiVites present an all-ebolavirus episode, tackling virology, epidemiology, and approaches to prevention and cure that are in the pipeline.

You can find TWiV #297 at www.microbe.tv/twiv.

Ebolavirus vaccines and antivirals

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.

TWiV 282: Tamiflu and tenure too

On episode #282 of the science show This Week in Virology, the TWiV team reviews a meta-analysis of clinical trial reports on using Tamiflu for influenza, and suggestions on how to rescue US biomedical research from its systemic flaws.

You can find TWiV #282 at www.microbe.tv/twiv.

TWiV 276: Ramblers go viral

On episode #276 of the science show This Week in Virology, Vincent meets up with Susan Baker and Tom Gallagher at Loyola University to talk about their work on coronaviruses.

You can find TWiV #276 at www.microbe.tv/twiv.

TWiV 270: Homeland virology

On episode #270 of the science show This Week in Virology, Vincent and Rich discuss avian influenza virus and an antiviral drug against smallpox with Dennis and Yoshi at the ASM Biodefense and Emerging Diseases Research Meeting in Washington, DC.

You can find TWiV #270 at www.microbe.tv/twiv.