GeoVax has consistently expanded its development programs to include clinical-stage programs in Coronavirus (SARS-CoV-2) as well as ongoing preclinical programs in hemorrhagic fever viruses (Ebola Zaire, Ebola Sudan, Marburg), Mpox, smallpox, Zika, and malaria. The breadth of vaccines in development and the ability to provide solutions to emerging infectious threats reflects the ability and broad utility of our technology platform.

Patients with compromised immune systems represent a large unmet need as current COVID-19 mRNA-based vaccines offer limited protection in this population. There are an estimated 23 million immunocompromised individuals in the U.S.* and 250 million+ worldwide** representing patients that received cancer treatment, HIV Positive, Chronic Kidney Disease and Solid Organ Transplant recipients.

 

COVID-19, caused by the SARS-CoV-2 virus, is a serious public health issue of worldwide threat and concern. The World Health Organization reports more than 757 million cases and nearly 7 million deaths worldwide. SARS-CoV-2 is an enveloped, single-stranded, positive-sense RNA virus belonging to the family Coronavidae within the genus beta-coronavirus. The genome of SARS-CoV-2 encodes one large Spike (“S”) protein that plays a pivotal role during viral attachment to the host receptor and entry into host cells. The S protein is the major principal target for vaccines against human coronavirus, including SARS-CoV-2, which results in COVID-19. Neutralizing antibodies targeting the receptor binding domain (“RBD”) subunit of the S protein block the virus from binding to host cells. Over 90% of all neutralizing antibodies produced in response to infection are directed to the RBD subunit.

 

 

There are currently approximately forty vaccines authorized for use in one or more countries around the world, including four in the United States. These vaccines are primarily designed to induce antibodies specific for the S protein of SARS-CoV-2 but rely on different mechanisms for presentation or expression of the S antigen, including recombinant proteins, whole inactivated virus, defective adenovirus vectors (three different types) or mRNA. Unfortunately, the continued adaptation and mutation of SARS-CoV-2 has resulted in the emergence of variants that are not optimally neutralized by vaccine-induced antibodies. This has required the adjustment of vaccine composition and the administration of multiple booster doses. Recently, the FDA indicated the likely need for continued vaccine adjustments and yearly boosters, similar to the approach used for influenza virus vaccines.

MVA is the vaccine vector platform utilized in a number of our vaccine candidates. There are several advantages to vaccines based on MVA as a platform. First, MVA has a large genetic coding capacity which provides the foundation for vaccines based on multiple SARS-CoV-2 proteins, including several which are highly conserved across the variants, instead of the singular focus on the continually changing S protein. This approach can induce immune responses with a greater breadth of specificity.

Second, MVA is known to effectively induce T-cell responses in addition to antibodies and such responses have been shown to result in more durability of the immune response.

Finally, MVA replicates minimally in mammalian cells which contributes to it being an extremely safe vaccine platform for human vaccines. As a result of the combination of these attributes, MVA is an ideal vaccine vector platform for the design of the next-generation COVID-19 vaccines, especially in targeting patient populations with compromised immune systems.

 

 

The CDC and other global public health agencies identify immunocompromised patients, including patients who have received therapeutic procedures for hematologic malignancy, as the highest risk for SARS-CoV-2 disease. SARS-CoV-2 infection can be very serious in this vulnerable population of hematology patients, including autologous (auto) and allogeneic (allo) hematopoietic cell transplant (HCT), and recipients of chimeric antigen receptor (“CAR-T”) cell therapies. Given the serious impact of other respiratory viruses in this vulnerable patient population, it is anticipated that hematology recipients of cell therapy may develop severe clinical disease, profoundly impacting the therapy outcomes, such as morbidity and survival. Increasingly, there is evidence of the high risk of severe morbidity, hospitalization and death resulting from SARS-CoV-2 in hematology patients. To date, there has been no clinical trial of an approved vaccine focused on immunocompromised patients. Thus, the efficacy and safety of a SARS-CoV-2 vaccine remains to be established in the different immunocompromised patient populations and it is likely that candidate SARS-CoV-2 vaccines may differ in their efficacy and safety for these patients.

 

Our vaccine candidate, GEO-CM04S1, is based on a synthetic, attenuated Modified Vaccinia Ankara (sMVA) vector expressing both spike (S) and nucleocapsid (N) antigens of the SARS-CoV-2 virus and was initially developed at the City of Hope National Medical Center (COH) for use in immunocompromised patients. In a placebo-controlled Phase 1 clinical trial of healthy adults conducted by COH, GEO-CM04S1 was shown to be safe and immunogenic. In November 2021, GeoVax entered into a license agreement with COH, granting GeoVax exclusive worldwide rights to further develop and commercialize the vaccine. 

 

GEO-CM04S1 is being studied in an ongoing Phase 2 clinical trial (NCT04977024) to evaluate its safety and immunogenicity, compared to either the Pfizer-BioNTech or Moderna mRNA-based vaccine, in patients who have previously received either an allogeneic hematopoietic cell transplant, an autologous hematopoietic cell transplant or chimeric antigen receptor (CAR) T-cell therapy. GEO-CM04S1 is the only SARS-CoV-2 vaccine that includes both S and N proteins to advance to a Phase 2 trial in cancer patients. MVA-vector-based vaccines tend to produce an immune response quickly – in less than 14 days – with only mild side effects. The trial is also the first to compare an investigational multi-antigenic SARS-CoV-2 vaccine to the current Food and Drug Administration (FDA)-approved mRNA vaccines from Pfizer-BioNTech and Moderna in people who are immunocompromised. Such patients have often shown a weak antibody response after receiving currently available COVID-19 vaccines.

 

 

Chronic lymphocytic leukemia (“CLL”) patients are recognized as a patient population having a high risk of severe disease, hospitalization and possible death as a result of a depleted immune system. They represent a patient group for whom current mRNA vaccines and monoclonal antibody (MAb) therapies appear inadequate relative to providing protective immunity. GeoVax supports a Phase 2 COVID-19 vaccine booster clinical trial (ClinicalTrials.gov Identifier: NCT05672355) among this critically high-risk patient population.

GEO-CM04S1 is being evaluated as a booster among CLL patients, having received an initial mRNA vaccine, evaluating GEO-CM04S1 vs an mRNA vaccine as a potentially more effective at inducing COVID-19 immunity in patients with poor humoral immune responses since MVA is recognized to strongly induce T-cell expansion even in the background of immunosuppression.

Targeting both the spike and nucleocapsid protein antigens broadens the specificity of the immune responses and protects against the loss of efficacy associated with the significant sequence variation observed with the spike antigen.

The study will examine the use of two injections of GEO-CM04S1 three months apart to assess immune responses in these vulnerable patients, with the Pfizer-BioNTech Bivalent vaccine as the control arm. The trial is expected to enroll approximately 80 patients. This investigator-initiated trial, referencing the GeoVax IND, is being primarily funded by a private family foundation with GeoVax supporting the analysis of samples.

The study has been welcomed by the CLL Society, a nonprofit dedicated to the unmet needs of those diagnosed with CLL/small lymphocytic lymphoma (SLL). We expect the CLL trial will further confirm the potential benefit of GEO-CM04S1 in this critically high-risk population of immunocompromised individuals.

Other Infectious Disease Development Programs

 

Mpox and Smallpox (GEO-MVA)

MVA was originally developed for use as a smallpox vaccine more than 30 years ago. MVA is the preferred vaccine for individuals with compromised immune systems as these individuals would be put at significant risk if administered the initial-developed smallpox vaccine. It is also approved as the vaccine for other orthopox vaccines, including Mpox. As such, an added potential benefit of our vaccines is that in those regions where Mpox or smallpox are of concern, vaccines built on an MVA vaccine platform will likely provide protection against both.

MVA is the vaccine currently used and stockpiled in the U.S. Strategic National Stockpile for immunization against the Mpox and smallpox viruses. Previously, GeoVax demonstrated that an experimental HIV vaccine, utilizing MVA as the vaccine vector, protected non-human primates challenged with a lethal dose of the Mpox virus. Further, in August 2022, the City of Hope team, which originally developed GEO-CM04S1, published results demonstrating that both their proprietary sMVA (synthetic MVA) and GEO-CM04S1 (referred to as “COH04S1” in the publication) elicited robust orthopoxvirus-specific binding and neutralizing antibody responses. The authors conclude that GEO-CM04S1 and sMVA represent unique vaccine candidates to control the unforeseen global Mpox outbreak.

In response to the global need to address the continued emerging threat from Mpox and the unique opportunity offered by MVA-based vaccines, GeoVax recently acquired rights from the NIH covering preclinical, clinical and commercial uses of the NIH-MVA against Mpox or smallpox viruses. The Company is now clarifying the development and regulatory pathways towards expanding the public health options available to reduce and manage the risk of Mpox worldwide.

 

Hemorrhagic Fever Virus Vaccines (Ebola Zaire, Ebola Sudan and Marburg)

Ebola (EBOV), formerly designated as Zaire ebolavirus), Sudan (SUDV), and Marburg viruses (MARV) are the most virulent species of the Filoviridae family, causing hemorrhagic fever illnesses with up to a 90% fatality rate in humans. The first EBOV outbreaks occurred in remote villages in Central Africa, near tropical rainforests. The 2014–2016 outbreak in West Africa was the largest and most complex Ebola outbreak since the virus was first discovered in 1976. There were more cases and deaths in this outbreak than all others combined. It also spread between countries, starting in Guinea then moving across land borders to Sierra Leone and Liberia. MARV outbreaks have been reported in Angola, Democratic Republic of the Congo, Kenya, South Africa (in a person with recent travel history to Zimbabwe) and Uganda. In December 2019, FDA approved the first live recombinant Ebola vaccine for prevention of Ebola disease by Zaire virus. This rVSV-ZEBOV showed safety concerns in Phase 1 trials and by virtue of being replication competent could pose threats to immunocompromised individuals, such as those infected with HIV living in West Africa where recent Ebola epidemics started.

To address the unmet need for a product that can respond to future hemorrhagic fever outbreaks, we are developing vaccines utilizing our GV-MVA-VLP™ platform. As previously noted, the MVA vector itself is considered safe, having originally been developed for use in immunocompromised individuals as a smallpox vaccine. We expect our vaccines may protect at-risk individuals against EBOV, SUDV and MARV, and the GeoVax GV-MVA-VLP™ approach could offer a unique combination of advantages to achieve breadth and safety of a pan-filo vaccine. In addition to protecting historically higher-risk populations in Africa, it is also intended to prevent the spread of disease to the U.S. and globally, and for preparedness against terrorist release of any of biothreat pathogens in the U.S. and globally.

Our initial preclinical studies in rodents and nonhuman primates for our MVA-VLP-EBOV vaccine candidate have shown significant levels of protection against lethal doses of EBOV. Recent studies in lethal challenge guinea pig models demonstrated that GeoVax vaccines MVA-VLP-SUDV and MVA-VLP-MARV conferred 100% protection from death. These vaccines were subsequently evaluated in a rigorous cynomolgus macaque infectious challenge model. Vaccination protected nonhuman primates from viremia, weight loss and death following challenge with a dose of Sudan or Marburg virus that is lethal in nonvaccinated animals. Evaluation of immune responses following vaccination demonstrated presence of both neutralizing antibodies and functional T cells, indicating a breadth of responses that combine for optimal protection. The nonhuman primate studies conducted in collaboration with NIAID and the U.S. Department of Defense (DoD) have been completed and clinical development programs are being defined with these same partners with a focus on potentially developing products for the U.S. Strategic National Stockpile.

 

Zika Virus

Zika disease is an emerging infectious disease caused by the Zika virus (ZIKV) and has been linked to an increase in microcephaly in infants and Guillain-Barre syndrome (a neurodegenerative disease) in adults. ZIKV is a member of the Flaviviridae family, which includes medically important pathogens such as dengue fever, yellow fever, Japanese encephalitis, tick-borne encephalitis, and West Nile viruses. Public health officials recommend avoiding exposure to ZIKV, delaying pregnancy, and following basic supportive care (fluids, rest, and acetaminophen) after infection.

To address the unmet need for a ZIKV vaccine, we are developing novel vaccine candidates constructed using our MVA platform. MVA has an outstanding safety record, which is particularly important given the need to include women of child-bearing age and newborns among those being vaccinated. 

Initial preclinical studies in rodents using GEO-ZM02 vaccine candidate demonstrated 100% single-dose protection against a lethal dose of ZIKV delivered directly into the brain. In rhesus macaques, vaccination with GEO-ZM02 induced immune responses that effectively controlled the virus replication despite the fact the vaccine is not designed to induce ZIKV neutralizing antibodies.  

In January 2023, GeoVax announced that the U.S. Patent and Trademark Office issued a Notice of Allowance for Patent Application No. 17/000,768 titled, “Method for Generating a ZIKV Immune Response Utilizing a Recombinant Modified Vaccinia Ankara Vector Encoding the NS1 Protein.” Preclinical studies demonstrated a single dose of GEO-ZM02 provided 100% protection against a lethal dose of Zika virus.