Hemorrhagic Fever Vaccines

About Ebola, Sudan, Marburg and Lassa fever virusesEbola (EBOV, formerly designated as Zaire ebolavirus), Sudan (SUDV), and Marburg viruses (MARV) are the current most virulent species of the Filoviridae family. They cause up to a 90% fatality rate in humans, and are epizootic in Central and West Africa with 28 outbreaks since 1976.  The 2013-16 Ebola outbreak caused 28,616 cases and 11,310 deaths (40% fatal) with the last case in a 2-year old boy who recovered in June 2016.  However, additional outbreaks are certain due to indigenous reservoirs of the virus (e.g. in fruit bats).  On May 11, 2017, a new Ebola outbreak was announced in the Democratic Republic of Congo which was ended on July 2, 2017 resulting in 8 cases, 4 of which were fatal (50% fatal).  Although the timing of the next filovirus outbreak cannot be predicted, it is certain that one will occur due to multiple factors such as: the zoonotic nature of the virus, weak health systems, high population mobility, cultural beliefs, burial practices and endemic infectious diseases such as malaria and Lassa fever (see below) that mimic early Ebola symptoms.

Lassa fever virus (LASV), a member of the Arenaviridae family, also causes severe and often fatal hemorrhagic illnesses in an overlapping region with Ebola. In contrast to the unpredictable epidemics of filoviruses, LASV is endemic in West Africa with an annual incidence of >300,000 infections, resulting in 5,000-10,000 deaths. Data from a recent sero-epidemiologic study suggest that the number of annual LASV cases may be much higher, reaching three million infections and 67,000 deaths, putting as many as 200 million persons at risk.

We believe an ideal vaccine against major filoviruses and LASV viruses must activate both humoral and cellular arms of the immune system. It must include the induction of antibodies to slow the initial rate of infection and a cellular immune response to help clear the infection. Moreover, it must address strain variations by providing broad coverage against potential epizootic filovirus strains, and it must be safe not only in healthy individuals (e.g. travelers or health care workers), but also in immunocompromised persons (e.g., HIV infected) and those with other underlying health concerns.

Despite significant progress being made with some experimental vaccines in clinical trials, none have been fully tested for both safety and efficacy. The world would benefit by being prepared with a multivalent filovirus vaccine, to prevent or alleviate the effects of the next epidemic.

Our Vaccines. To address the unmet need for a product that can respond to future filovirus epidemics and potentially end LASV infections in West Africa, we are developing an innovative Tetravalent Vaccine (TV) utilizing our proven Modified Vaccinia Virus Ankara-Virus Like Particle (MVA-VLP) platform. We are addressing strain variations, and induction of broad humoral and cellular response through development of 4 monovalent vaccines, which can be used individually against a specific disease or potentially be blended to provide broad coverage. The MVA vector is highly safe, having been developed for use in immunocompromised individuals. It has had excellent safety in clinical trials in immunocompromised (~1000) as well as normal (>120,000) people and is currently licensed by Bavarian Nordic for use as a smallpox vaccine.

Our TV vaccine program is seeking to generate VLPs by expressing both GP and matrix proteins (VP40 for filoviruses, Z for LASV) in single vectors for each of its target viruses. It is being designed to elicit protective antibodies against GP as well as protective T cells against GP plus the more conserved VP40, or Z, matrix proteins. It is expected to not only protect at risk individuals against EBOV, SUDV, MARV, and LASV; but also, potentially reduce or modify the severity of other re-emerging filovirus pathogens such as Bundibugyo, Ivory Coast, and Reston viruses, based on antigenic cross reactivity and the elicitation of T cells to the more conserved matrix proteins. Thus, the GeoVax MVA-VLP-TV approach offers a unique combination of advantages to achieve breadth and safety of a pan-filo/LASV vaccine. In addition to protecting people in Africa, it is intended to prevent the spread of disease to the US, as with the last outbreak, and for preparedness against terrorist release of any of these four bio-threat pathogens (EBOV, SUDV, MARV, and LASV). The initial markets for the TV vaccine are both NGOs such as GAVI, the Vaccine Alliance and the Bill & Melinda Gates Foundation, as well as US and foreign governments.

Our initial preclinical studies in rodents and nonhuman primates for our first vaccine candidate (EBOV) have shown 100% protection against a lethal dose of Ebola virus upon a single immunization.  The results of these studies have been submitted for publication in a peer reviewed journal.

Similar to our Ebola vaccine, our Lassa vaccine candidate, GEO-LM01, provided 100% protection to mice. During testing, mice were given a single-dose vaccination of GEO-LM01 into muscle tissue, then infected with 1000 Plaque Forming Units of the challenge virus by intracranial inoculation. All vaccinated mice survived whereas all unvaccinated mice died within one week of infection. Vaccinated animals produced a strong T cell immune response against LASV at 10 days post vaccination. The study was conducted at the Institute of Human Virology at the University of Maryland School of Medicine in Baltimore. A repeat of the study confirmed the findings. Today, no treatment or vaccine is available to stem LASV epidemics, even though LASV kills more people in one year than the EBOV did in the last 41 years after its first epidemic in 1976 in West Africa. Lassa fever has a greater human impact than any other hemorrhagic fever virus, except for dengue fever, and despite this clear need, no vaccine has yet entered human clinical trials. We have submitted a fast track grant application to support advanced preclinical testing of our Lassa vaccine candidate and the initiation of human clinical trials in near future.

Innovation. The innovation in our MVA-VLP-TV vaccine is in the design of the individual vectors, which use unique MVA shuttle vectors combined with appropriate strength promoters and codon optimizations to achieve genetically stable vectors expressing high levels of filovirus and LASV VLPs. We have developed three different generations of shuttle vectors, during a 15 year collaboration with NIH in developing MVA/HIV vaccines expressing VLPs. VLPs, expressed by MVA, in turn, form a basis of a highly effective vaccine, as the VLPs are made in the person being vaccinated and do not have to be purified, reducing manufacturing costs. Moreover, they can express native forms of membrane-displayed viral envelope glycoproteins. The array of GPs on the VLPs is highly favorable for cross-linking B cell receptors and initiating an Ab response. The expression of VP40 or Z in infected cells stimulates CD8 T cell responses against the relatively conserved matrix proteins broadening protection.

Many consider MVA a boosting, not a priming vaccine. However, our MVA-expressed VLPs are very good priming vaccines. In guinea pigs, a single dose of the GeoVax EBOV vaccine (MVA/Z-VLP) raises the same levels of Abs as raised by a single dose of a competitor's recombinant VSV vaccine expressing the EBOV GP. In non-human primates, a single dose of our Ebola vaccine protected 100% of animals against a lethal dose of Ebola virus.