Excerpt from Hunter’s Tropical Medicine and Emerging Infectious Diseases E-Book

Paramyxoviruses (Nipah, Hendra, Menangle)

There is phylogenetic evidence that bat paramyxoviruses were ancestors to all major extant paramyxoviruses, including measles, mumps, parainfluenza, respiratory syncytial virus, and important veterinary pathogens. Three emerging paramyxovirus infections have been described for which bats are the likely natural reservoirs, and domestic horses and pigs have proved to be the amplifying vectors for human infection. Hendra and Nipah viruses are Henipaviruses; Menangle is a Rubulavirus.

Hendra Virus

In 1994, there was an outbreak of fatal respiratory disease in horses and humans in Australia, attributed to a new pathogen, Hendra virus, whose natural reservoir is Pteropus spp. (P. alecto, P. poliocephalus, P. scapulatus, P. conspicillatus). Since 1994, there have been 60 outbreaks of Hendra in the northeastern coastal region of Australia, causing the deaths of 102 horses and four of seven human cases, including two veterinarians.

Nipah Virus

In 1998, there was an epidemic of encephalitis in Malaysia and Singapore affecting pigs and pig handlers in whom the case fatality was more than 40%. The causative virus, named Nipah after an affected village, is closely related to Hendra virus. Pteropus vampyrus and Pteropus hypomelanus are the natural reservoirs. In 2001 a geographically distinct strain of Nipah virus emerged in West Bengal and Bangladesh, causing respiratory as well as encephalitic symptoms, with subsequent annual outbreaks and case fatality of more than 74%. Transmission in the original Malaysia/Singapore epidemic was via infected pigs, whereas in India and Bangladesh it was by drinking infected date palm sap or by human-to-human contact. In 2018 there was a Nipah virus (Bangladesh lineage) epidemic in Kozhikode and Malappuram districts of Kerala, South India. There were 23 cases with a 91% case fatality rate. Apart from the index case, who was probably infected by a pet Pteropus giganteus, transmission was nosocomial, probably through aerosol spread by coughing. So far, more than 600 human cases of Nipah virus encephalitis have been diagnosed. The epidemics have been attributed to disruption of Pteropus ecology by deforestation (e.g., building the new Kuala Lumpur airport), which displaced the bats from their traditional roosts to agricultural areas where they have contact with domestic animals and humans. In Bangladesh and India, where there have been >150 deaths, human-to-human transmission within families has been inferred.

Menangle and Tioman viruses have been isolated from Pteropus spp. in Australia and Malaysia and from sick pigs. Influenza-like illness in pig farmers with Menangle seroconversion has been reported.

Prior to the 2014 outbreaks of Ebola in west Africa, Ebolavirus disease (EVD or EHF) outbreaks were rural, and through aggressive contact tracing were effectively contained and ended. The source host for this filovirus was then and continues to be unknown.

Then in 2014, the virus got into the urban areas of several west African countries. The epidemic was traced back to an eighteen-month-old boy in Guniea. At that time, Médecins Sans Frontières and Samaritan’s Purse were the only two organizations responding clinically on the ground in the Liberia, Guinea, and Sierra Leone areas. The outbreak was much larger than any before since previous occurrences were rural and not urban. Médecins Sans Frontières and Samaritan’s Purse were taxed to the breaking point and the outbreak in Guinea, Sierra Leone, and Liberia became the largest in history dwarfing all previous ones.

The development of the Ebola vaccine is far from recent and really began in the mid 1990s. Prior that time, vaccines were based on sub-units of the infectious agent. That is, virus or bacteria had to be grown, harvested and only the “active” proteins retrieved which were included in the vaccine. The earlier lessons of the Cutter Incident with the polio vaccine and the high frequency of side effects with the whole cell pertussis vaccine demonstrated the need for a more targeted approach.

In the mid-1990s, Katalin Karikó, a Hungarian-born scientist, pioneered a new approach using mRNA instead of sub-units. Rather than collecting proteins from viruses and bacteria grown in living tissues, her idea was to develop a vaccine using the specific mRNA which coded very specifically for things like the spikes on viruses which attached them to the host cell membrane which then engulfed and “swallowed” the virion. If antibodies to these spike proteins were present already, then virus particles could never attach and never be engulfed by the host cell.

Karikó’s task was to somehow get the mRNA that coded for these spikes into the host cell whereby only the spikes would be produced. Once presented to the immune system, the proper antibody would be made and memorized. Future challenges by the actual virus then would be met swiftly with antibodies attacking the spike proteins preventing infection of the host cell. The University of Wisconsin had already proved this technique worked in mice in 1990.

The problem of creating mRNA was the main issue. Genomic sequencing became partner to all this as sequencing wholesale DNA and RNA strands became possible and very quick. It took only about 48 hours to sequence the mRNA for SARS-CoV-2 in 2019. A second problem with mRNA is how quickly it is degraded and disposed of outside the host cell. A virion with the spike proteins easily carried that mRNA code into the host cell, but simply injecting mRNA into a person won’t do the same.

With the 2014 Ebola outbreak, vaccine development first started using a viral vector to get the mRNA into the host. The idea is to attach the target mRNA to that of another virus which is not lethal and mostly innocuous. That virus would then be the vector by which the host cell would then produce the target spike protein that would in turn lead to antibody production against Ebolavirus.

In the 1990s, John “jack” Rose at Yale used a livestock virus called VSV (vesicular stomatitis virus) as this viral vector. Heinz Feldmann was instrumental in fusing the key Ebola mRNA onto VSV at the Philipps-Universität Marburg in Germany. This vaccine was called rVSV-ZEBOV. He tested it in animals before leaving the Canada Nation Microbiology Laboratory in Winnipeg in 2008. Steven Jones, an associate of his whose name is on the Ebola vaccine patent, began development of human-grade vaccine for the initial testing trials.

As the 2014 Ebola epidemic unfolded, Gary Kobinger, the head of special pathogesn at the National Laboratory in Winnipeg, was watching. His team had been working on the Ebola vaccine for years which showed great promise in animal testing. Vaccine development had gone so far as to produce one ready for human trials. The WHO declined his offer of the vaccine, however, and probably out of Africa’s history of unethical vaccine development by western entities years earlier with polio.

Essentially as a result of the 2014 Ebola outbreak, Merck finally picked up rVSV-ZEBOV, and the first viral vector vaccine for Ebola was branded as Ervebo. The VSV virus vector would go on into research for flu, mealses, SARS, and ZIKA vaccines. The vaccine was initially approved for compassionate use in 2018. It proved highly effective, and was FDA approved in 2019.

In the 2014 epidemic, both Dr. Kent Brantly and Nancy Writebol working for Samaritan’s Purse in Liberia contracted Ebola Zaire (Facing Darkness). This was, of course, before the Ervebo vaccine was available. However, another technology called ZMapp was already in testing and was available for experimental use.

ZMapp developed by Mapp Biopharmaceutical is not a vaccine, but rather three plant-made monoclonal antibodies which attack the Ebola virus. The tobacco plant Nicotiana benthamiana is infected with a viral vector. There are a number of plant viruses that are effective vectors such as tobamoviruses, Potexviruses (e.g. Potato Virus X) , Tobraviruses (e.g., tobacco rattle virus), Geminiviruses (e.g., bean yellow dwarf virus), and Comoviruses (e.g. cowpea mosaic virus).

ZMapp was effective in saving 100% of rhesus macaques infected with Ebola even up to 5 days before administration. Many animals already showed symptoms and had Ebola-driven laboratory aberrations before the drug. The drug was given to both Dr. Brantly and Writebol. They both survived Ebola Zaire. Miguel Pajares, a Spanish priest, received the third course of ZMapp but subsequently died from Ebola.

Viral vector vaccines led to the development of newer mRNA vaccines which have a lipid coating. This coating similarly acts like a virion so that the virus spike protein is manufactured from the mRNA and then released without harming the host cell. The immune cells then process the spike protein and create antibodies to it. Free of the overwhelming assault of viruses like Ebola and SARS-CoV-2, the immune system is equipped to fight the infection without ever having been infected with the pathogen. mRNA vaccines may well signal newer, safer, and more effective measures than many current vaccines.¹

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