The first generation of SARS-CoV-2 vaccines rolled out in record time in 2020, providing initial first-line protection against COVID-19. However, as COVID-19 continues to be a worldwide health problem, researchers are urgently investigating new vaccines to provide more potent and durable protection, including protection in various populations of patients, for whom the first-generation vaccines are insufficient. While the first-generation vaccines provided an initial line of protection, there is a lot more to do.
To provide more comprehensive protection against SARS-CoV-2, my company GeoVax is advancing a new generation of vaccines to provide robust and broadly specific antibody and T-cell responses, in contrast to first-generation vaccines that focus primarily on antibody immunity directed to a single viral antigen, the Spike (S) protein. The company currently has two Phase II clinical trials underway, with a unique, dual-antigen SARS-CoV-2 vaccine (GEO-CM04S1) that has potential to address the gaps left by the first-generation S-based vaccines.
The dual-antigen vaccine builds on the early successes from first-generation vaccines to provide more potent, broadly specific and durable protection. This includes protection against emerging variants and efficacy to safeguard vulnerable populations. Developed by the vaccine team at City of Hope National Medical Center (see below), GeoVax licensed exclusive worldwide rights of the vaccine in November 2021. Since then, we have focused on advancing and expanding the clinical development of GEO-CM04S1 in patient groups with unmet needs.
Advantages and limitations of original mRNA vaccines
The original mRNA vaccines developed by Moderna and by Pfizer/BioNTech helped mitigate a deadly pandemic. Fortunately, mRNA technology was well suited for a quick response, allowing rapid development of the vaccines and scaled-up production. As a result, mRNA technology provided the initial necessary public health vaccines to tamp down the pandemic.
Still, these first-generation vaccines have some limitations. First, they are based on only a single coronavirus protein—the S protein—which results in the generation of a relatively focused immune response. Second, the duration of the antibody responses is short-lived, which has required the administration of multiple booster doses, with only tepid uptake by the general public. Third, the original vaccines were designed to target the original Wuhan coronavirus strain, which didn’t provide a means to address continuous viral evolution.
This last limitation is critical because, as the virus evolved from Wuhan to Delta to Omicron (and many subsequent sub-strains), the neutralization efficiency of the antibodies induced by the original vaccine began to wane. This required the development of the latest iteration of the mRNA vaccines for use as boosters that target S proteins from both Wuhan and Omicron—boosting the response to the old strain and inducing new antibodies specific to the Omicron S protein mutations.
This need to adjust the vaccine to address new variants could go on indefinitely. In 2023 or 2024, there could be a call for a trivalent booster to again address the latest changes (bivalent boosters of Moderna and Pfizer/BioNTech were approved August 31.) At some point there may be a desire for a quadrivalent iteration, as is the current situation for influenza vaccines. The public health apparatus is essentially chasing variants and concerningly, with each additional booster recommended, public confidence further wanes relative to booster acceptance.
As noted, another issue is the durability of response. While mRNA vaccines produce robust antibody responses following the initial two doses, for unknown reasons these responses are characterized by a relatively short lifespan—the primary impetus for the serial boosters.
A third problem is distribution. The mRNA vaccines must be maintained in frozen-state, ultra-cold temperatures for shipment and storage. While this challenge has been successfully addressed in highly developed nations, it remains a logistical problem for distribution and use in low- and medium-income countries and remote regions that don’t have the required infrastructure. This has led to a recognized disparity in vaccine penetration in different parts of the world.
When these limiting issues are considered together, it becomes obvious that next-generation SARS-CoV-2 vaccines that produce broader immune responses—both antibodies and T cells—specific to multiple viral proteins, instead of relying solely on the mutable S protein, would mitigate the need to chase variants. The use of other vaccine platforms that induce more durable immunity would also provide better care for vulnerable populations. The use of other vaccine platforms that don’t require frozen shipment and storage would also provide a means to address some of the current distribution problems.
Creating a dual-antigen vaccine
The GeoVax next-generation, dual-antigen vaccine starts with its own vaccine vector based on—modified vaccinia Ankara (MVA). MVA was developed initially for use as a smallpox in immunocompromised individuals. As a result, MVA is recognized for both its potency and safety. MVA is an ideal vaccine vector, containing ample genomic space to insert the necessary coronavirus genes encoding multiple different proteins that, when expressed in the body of the vaccine recipient, induce the immune responses to all of the expressed antigens.
The GeoVax MVA-vectored dual-antigen vaccine encodes the S protein, and the nucleocapsid (N) protein to induce both antibody and robust T-cell responses. Adding the highly immunogenic N protein to the vaccine is particularly important because it is highly conserved amongst SARS-CoV-1 variants, which are much more genetically stable and make it a more stationary target for the immune system. Recent reports on animal studies completed by independent academic groups have clearly documented the value of immune responses to the combined S + N proteins for mediating protection against emerging variants, including Omicron.
In addition, the MVA vector is a highly effective and potent vaccine platform. The body identifies MVA as a virus and alerts the immune system (although it poses no danger). This augments the immune responses to the S and N proteins, known as an adjuvant effect. This adjuvant effect is also reflected in immune responses that are highly durable.
The dual-antigen MVA-vectored vaccine is a potential game-changer on many levels. First, the MVA vector increases the breadth, magnitude and duration of the immune response. Specifically, combining the N and S proteins expands the immune responses to SARS-CoV-2. Second, the vector vaccine platform effectively induces both antibodies and T cells. Equally important, targeting the conserved N protein increases the effectiveness of immune responses against variant forms of the virus. On a logistical level, the MVA-vectored vaccine is more stable than mRNA vaccines and remains stable for weeks under normal refrigeration. This removes the complexity of shipping vaccines to remote areas that lack the infrastructure to keep it super cold.
In a Phase I safety and immunogenicity clinical study, conducted at City of Hope and published in The Lancet Microbe, three healthy cohorts received low, medium and high doses of the dual-antigen MVA-vectored vaccine. The vaccine proved to be safe with minimal side effects commonly associated with vaccination. While the trial wasn’t designed to prove efficacy, researchers did show S and N specific antibody and T-cell responses were induced after a single vaccine dose and boosted with a second dose, regardless of dose levels.
The vaccine is now being evaluated in Phase II clinical studies in patients with blood cancers and leukemia who are undergoing therapy, to test whether it can induce effective immune responses in immunocompromised populations, in a direct, randomized comparison against the mRNA vaccines. These are critical patient groups, for whom the current SARS-CoV-2 vaccines are not generating optimal immune responses. Many patients with chronic lymphocytic leukemia, B-cell leukemia and similar conditions have trouble producing antibodies. A study published in 2021 found that 46% of patients with hematologic cancers did not produce significant antibodies. This is a huge problem for the more than 185,000 Americans with blood cancers. For GeoVax, this provides a potential opportunity to negotiate an accelerated regulatory review path which would include the use of immune response data as a surrogate measurement of efficacy.
The dual-antigen vaccine is also in a second Phase II clinical trial as a universal booster for the approved SARS-CoV-2 vaccines. This dose-escalation study is designed to expand upon the Phase I study and specifically to evaluate the vaccine’s safety and immunogenicity as a booster shot in healthy participants. The study will soon be fully enrolled with safety and immune response data available mid-2023.
Next: A pan-coronavirus vaccine
GeoVax is taking this multi-antigen thinking a step further with a pan-coronavirus vaccine. Like the dual-antigen vaccine, this approach involves the use of the MVA vector but includes the use of the S protein and other viral structural proteins, such as the Membrane and Envelope proteins, and potentially highly conserved nonstructural proteins.
Delivering multiple structural proteins together adds a new element which can further boost the immune response—virus-like particles (VLP), which are produced inside the body of the vaccine recipient. To the body, these VLP look like actual coronavirus particles, though they are incapable of spreading infection. As a result, the immune system is tricked to believe it is faced with an active infection and ratchets up the optimal immune response.
With both the dual-antigen vaccine and its more sophisticated pan-coronavirus cousin, the strategy is clear: hit the virus from as many angles as possible. By incorporating these different elements, GeoVax is working towards immunologic balance—maximizing the immune response and minimizing the microbe’s ability to evade it. This should provide a new set of tools for clinicians, public health officials and others to begin the long-awaited process of both eradicating this disease and preparing for new threats.
Mark J. Newman PhD, is the Chief Scientific Officer at GeoVax. He can be reached at [email protected]