TWiV Special: Gary Nabel on World AIDS Day 2016

For World AIDS Day 2016, Vincent speaks with Gary Nabel, Chief Scientific Officer at Sanofi and former Director of the Vaccine Research Institute of NIAID, about his career and his work on HIV vaccines.

You can find this TWiV Special at microbe.tv/twiv, or listen and watch here.

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TWiV 413: Partnerships not parachutes

From the EIDA2Z conference at Boston University, Vincent, Alan and Paul meet up with Ralph Baric, Felix Drexler, Marion Koopmans, and Stacey Schultz-Cherry to talk about discovering, understanding, protecting, and collaborating on emerging infectious diseases.

You can find TWiV #413 at microbe.tv/twiv, or watch or listen here.

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TWiV 403: It’s not easy being vaccine

The TWiV team takes on an experimental plant-based poliovirus vaccine, contradictory findings on the efficacy of Flumist, waning protection conferred by Zostavax, and a new adjuvanted subunit zoster vaccine.

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Whole plant cells producing viral capsid protein as a poliovirus vaccine candidate

poliovirusAlthough the use of the live, attenuated (Sabin) poliovirus vaccines has been instrumental in nearly eradicating the virus from the planet, the rare reversion to virulence of these strains has lead to the World Health Organization to recommend their replacement with inactivated poliovirus vaccine (IPV). Unfortunately IPV is also not without shortcomings, including high cost, failure to induce intestinal immunity, and the need to keep the vaccine at low temperatures. An experimental poliovirus vaccine produced in plants could overcome these problems.

A new vaccine candidate was made by producing the poliovirus capsid protein VP1 in the chloroplast of tobacco plants (nuclear-directed antigen synthesis is often inefficient). VP1 was fused to the cholera toxin B (CTB) subunit which allows good transmucosal delivery of the protein. Leaves were freeze dried, ground to a powder, mixed with saline and fed to mice after subcutaneous inoculation with IPV. The results show that boosting with the plant-derived VP1-CTB protein lead to higher antibody neutralizing titers (against all three poliovirus serotypes) both in the blood and in fecal extracts, compared with mice inoculated with IPV alone.

The VP1-CTP protein within lyophilized plant cells was stable for 8 months at ambient temperatures. If immunogenicity is maintained under these conditions, it would eliminate the need for a cold chain to maintain vaccine potency, an important achievement.

The authors propose that plant-produced VP1-CTP protein could substitute for IPV once the use of OPV is discontinued. Whether this suggestion is true depends on confirmation, by clinical trial, of these findings in humans. Furthermore, oral administration of VP1-CTP plant cells alone produces no serum neutralizing antibodies, and whether VP1-CTP boosts immunity in OPV recipients remains to be determined. Because VP1-CTP does not provide protection in children who have never received IPV or OPV, it cannot be used if poliovirus circulation continues indefinitely in the face of a growing cohort that has not been immunized with IPV or OPV. Nevertheless the technology has promise for the development of other vaccines that are inexpensive and do not need low temperature storage.

TWiV 402: The plight of the bumblebee

Polio returns to Nigeria, Zika virus spreads in Miami, and virus infection of plants attracts bumblebees for pollination, from the virus gentlepeople at TWiV.

You can find TWiV #400 at microbe.tv/twiv, or listen below.

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TWiV 401: Vector victorious

Zika virus spreads in the USA, a Zika virus DNA vaccine goes into phase I trials, and how mosquito bites enhance virus replication and disease, from the friendly TWiFolk Vincent, Dickson, Alan, and Kathy.

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Antibodies aid dengue and Zika virus infection

Antibody dependent enhancementFlaviviruses are unusual because antibodies that cross-react with different viruses can enhance infection and disease. This property, called antibody-dependent enhancement or ADE, has been documented to occur among the four serotypes of dengue virus. It has implications for infection with or vaccination against Zika virus or dengue virus.

Earlier this year (virology blog link) it was shown that antibodies to dengue virus – in the form of serum from infected patients, or two human monoclonal antibodies – bind to Zika virus and can enhance infection of Fc-receptor bearing cells (Fc receptors bind the antibody molecule, allowing uptake into cells – illustrated). When the antibodies to dengue virus were omitted, Zika virus barely infected these cells. The conclusion is that dengue antibodies enhance infection of cells in culture by Zika virus.

This early work was first published as a preprint on the bioRxiv server – which lead some to criticize me for discussing the work before peer review. However, I subjected the paper to my own peer review, of which I am entirely capable, and decided it was worthy of discussion on this blog.

The results have now been confirmed by an independent group (paper link). Sera from patients that were infected with dengue virus, as well as dengue virus specific human monoclonal antibodies, were shown to bind Zika virus and enhance infection of Fc receptor bearing cells. These are the same findings of the group who first published on bioRxiv. That paper still has not been published – apparently it is mired in peer review, with many new experiments requested. I do hope that none of the authors of the second paper are involved in delaying its publication – something that happens all too often in science. As a colleague once remarked, ‘the main function of peer review is to prevent your competitors from publishing their work’.

Whether or not antibodies to dengue virus enhance Zika virus disease in humans is an important unanswered question.

If you are wondering whether antibodies to Zika virus can enhance dengue virus infection, the answer is yes (paper link). Monoclonal antibodies were isolated from four Zika virus-infected patients, and shown to enhance infection of Fc receptor bearing cells with either Zika virus or dengue virus. Furthermore, administration of these antibodies to mice before infection with dengue virus led to severe disease and lethality, a demonstration of antibody-dependent enhancement in an animal model.

Of interest is the finding that ADE mediated lethality in this mouse model can be completely prevented by co-administering the same antibody that has been modified to block binding to Fc receptors on cells. This result suggests a modality for treating patients with enhanced disease caused by either dengue virus or Zika virus.

These observations suggest that we need to be careful when deploying vaccines against Zika virus or dengue virus – it is possible that the antibody response could enhance disease. Recently a dengue virus vaccine called Dengvaxxia was approved for use in Brazil, Mexico, and the Philippines. However, the vaccine is not licensed for use in children less than 9 years of age because in clinical trials, immunization lead to more severe disease after infection compared with non-immunized controls. Analysis of the clinical trial data (paper link) indicates that seronegative individuals of all ages were at increased risk for developing severe disease that requires hospitalization. The authors suggest that severe disease is a consequence of enhancement of infection caused by antibodies induced by the vaccine (see CIDRAP article for more information).

These observations lead to the question of whether immunization against dengue and Zika viruses might enhance disease caused by either virus. Could a solution to this potential problem be to use a vaccine that combines the four serotypes of dengue virus with Zika virus? If so, the dengue virus component should not be Dengvaxia, but possibly another vaccine (e.g. TV003 – virology blog link) that does not induce disease enhancing antibodies.

Zika virus vaccine

The first experimental Zika virus vaccine has been published, and in this episode of Virus Watch, I explain how it works – it’s a DNA vaccine – and I compare it with all the other vaccines out there.

TWiV 396: Influenza viruses with Peter Palese

TWiVVincent speaks with Peter Palese about his illustrious career in virology, from early work on neuraminidases to universal influenza virus vaccines, on episode #396 of the science show This Week in Virology.

You can find TWiV #396 at microbe.tv/twiv, or listen below.

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Zika virus and mosquito eradication

Aedes aegyptiThe Aedes aegypti eradication campaign coordinated by the Pan American Health Organization led by 1962 to elimination of this mosquito from 18 countries, including Brazil. Ae. aegypti transmits not only Zika virus, but dengue virus, chikungunya virus, and yellow fever virus. Could control measures be implemented today to achieve similar control of this mosquito? Two articles in PLoS Neglected Tropical Diseases revisit the successful PAHO mosquito control campaign and suggest that its approaches should be revived.

The elimination of Ae. aegypti in 18 countries, which was accompanied by a marked reduction in dengue hemorrhagic fever, was achieved by removing mosquito breeding sites or spraying them with DDT. Determining whether households harbored such breeding sites was essential for the effectiveness of the campaign.

The United States did not participate in the PAHO campaign, even though Ae. aegypti was (and still is) present in that country, and was a vector for outbreaks of dengue fever from the 1920s through the 1940s. Peter Hotez (link to paper) cites a “lack of funds and political will” and “logistical difficulties due to lack of access to private homes or cultural norms of privacy in the US”. As a consequence, by 1970 the US became one of the last reservoirs of Ae. aegypti in the Americas.

Eventually the PAHO campaign fell apart and Ae. aegypti returned, followed by outbreaks of dengue fever in the 1980s in Latin America and the Caribbean, and Chikungunya virus and Zika virus in 2013.

Hotez argues that while control of Ae. aegypti is labor intensive and involves house-to-house spraying, PAHO demonstrated its feasibility. He further suggests that by not participating in the PAHO campaign, the US failed to establish a generation of mosquito control expertise, which is now needed as Zika virus and other mosquito-borne viruses threaten to spread. He calls for an “unprecedented campaign against the Ae. aegypti mosquito”. However, he does not specify exactly what kind of control should be implemented, only saying that “these activities might not closely resemble the Latin American programs of the 1960s”.

Paul Reiter (link to paper) believes that the success of the PAHO campaign “can be attributed to a single aspect of the behavior of the mosquitoes: female Ae. aegypti do not lay all their eggs in one basket”, but rather place them at multiple locations. During the PAHO campaign, infested containers were identified and sprayed with DDT, increasing the likelihood that a female would lay eggs at a site that had been treated. This approach is called perifocal.

The current use of fogging machines to spray residential areas with insecticides has a low impact on mosquito populations, according to Reiter, because they only work for a few minutes when the droplets are airborne. He believes that we should return to perifocal treatments to eliminate mosquitoes, but not using DDT. Rather he suggests the use of other, novel insecticides, such as crystals of deltamethrin embedded in a rain and sun-proof polymer that ensures release for three months.

Reiter acknowledges that long-term use of insecticides leads to resistance, in which case we should turn to the new anti-mosquito approaches that are being developed, including the release of mosquitoes containing Wolbachia bacteria or a lethal gene. But he indicates that these approaches “are some way from mass application”, and meanwhile, perifocal approaches could reduce mosquito populations (although the newer insecticides would first need to be tested).

The best way to prevent viral infection is with a vaccine, but one for Zika virus is likely years away. Meanwhile, mosquito control can make a difference, as it could for the next emerging virus well before a vaccine can be developed.