NIAID’s VRC, S. Africa’s Afrigen Kick Off Vaccine-Sharing Efforts
Training Aimed at Making mRNA Technology Available Globally 

A team of vaccine production experts from South Africa recently finished training in Maryland as part of a global mRNA vaccine collaboration. The experts are working with scientists at NIAID’s Vaccine Research Center (VRC) to produce vaccines against a list of troubling infectious diseases.

The mRNA vaccine platform, which became commonly used during the COVID-19 pandemic, works by delivering a piece of genetic material to cells that instructs the body to make a protein fragment resembling one from a target pathogen (such as a virus). The immune system then recognizes and remembers the fragment, enabling it to mount a strong response if the body is exposed to that pathogen. The mRNA vaccine production process involves inserting the selected virus protein gene into a plasmid (a circular piece of DNA), the production of which was the topic of the visit from the South African scientists.

The seven-member team from Afrigen Biologics and Vaccines, a biotechnology company based in Cape Town, South Africa, arrived on July 21 for two weeks of collaboration and learning with VRC scientists. They focused on vaccine manufacturing at the VRC’s Vaccine Clinical Materials Program in Frederick, Maryland. Specific aspects included topics such as: inoculum growth, nutrient feeding, quality control, and other steps needed to make an mRNA vaccine. The Afrigen team also met with VRC leadership, including the recently appointed VRC Director, Dr. Ted Pierson. 

The visit represented a significant milestone for an ongoing research collaboration established in March 2022 between NIAID and Afrigen. Their objective is to share knowledge, expertise, and data to expedite mRNA vaccine production globally. As part of the collaboration, NIAID – specifically scientists at the VRC – are making plasmid DNA that will be used for Afrigen’s in vitro transcription process. Additionally, the VRC is providing technology transfer and training on plasmid DNA manufacturing, which the Afrigen group observed during the visit. In turn, Afrigen is sharing knowledge and expertise with NIAID scientists about the in vitro transcription and lipid nanoparticle formulation processes. The mutually beneficial scientific collaboration will advance each institution’s work toward establishing mRNA vaccine production capabilities to support their respective missions.

The World Health Organization, the COVAX Vaccine Manufacturing Taskforce, and the Medicines Patent Pool established a formal agreement in July 2021 to build capacity in low- and middle-income countries to make mRNA vaccines, now known as the mRNA technology transfer programme. Afrigen was chosen as a center of excellence and training, or “technology transfer hub,” as part of the mRNA technology transfer programme. The hub is designed to improve the health and security of member nations by creating sustainable, locally owned mRNA vaccine manufacturing in those nations. Because mRNA vaccines can be cheaper to produce, quickly developed in response to outbreaks, and easily modified when new variants of pathogens emerge, the ability to produce these vaccines in low- and middle-income nations will contribute significantly to global health security.

Afrigen is working to establish mRNA vaccine production technology—initially for a COVID-19 vaccine candidate—and will work with local partners to conduct research to evaluate the vaccines, along with manufacturing the vaccines at scale. The eventual goal is to be able to share this established process with manufacturers across multiple countries. 

Though the effort began with COVID-19 in mind, the scientists are mutually hoping to use the mRNA vaccine platform to develop and test vaccines against an array of infectious diseases found globally, such as HIV, tuberculosis, malaria, influenza, cancer-associated viruses and more.

Afrigen scientists spent time getting to know colleagues at the Vaccine Research Center’s Vaccine Production Program (VPP) and Vaccine Clinical Materials Program (VCMP), including during a meet-and-greet with VRC leadership and staff at the VCMP pilot plant in Frederick, Maryland.

Credit: NIAID

This blog is cross-posted from HIV.gov. 

On Tuesday at the International AIDS Society’s 12th Conference on HIV Science (IAS 2023), HIV.gov continued our conversations about research highlights, including a focus on the latest about HIV vaccines. We also heard an update from the NIH Office of AIDS Research.

NIH’s Carl Dieffenbach, Ph.D., Director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases (NIAID), spoke with Louis Shackelford, M.P.H., about HIV vaccine studies being discussed at IAS 2023 and potential roles for broadly neutralizing antibodies (or bNAbs). Louis is the Acting Director for External Relations at the NIH-supported HIV Vaccine Trials Network (HVTN) and COVID-19 Prevention Network. Noting it is an exciting time in HIV vaccine research, Carl explained that scientists are exploring how to take what we have learned about bNAbs, which prevented acquisition of some HIV strains, and turn that into an HIV vaccine. In addition, Carl and Louis discussed how bNAbs are being studied for use in HIV treatment and even, possibly, a cure. View their conversation below:

Bill Kapogiannis, M.D., Acting Director of NIH’s Office of AIDS Research (OAR), spoke with Catey Laube, Section Chief for HIV, STIs, Allergy, Immunology, and Transplantation in NIAID’s Office of Communications and Government Relations. OAR coordinates the scientific, budgetary, legislative, and policy components of HIV/AIDS research across NIH’s institutes and centers. Bill discussed the importance of the results from the NIH-supported REPRIEVE trial presented yesterday at the conference. The global study found that statins, a class of cholesterol-lowering medications, may offset the elevated risk of cardiovascular disease experienced by people with HIV by more than a third, potentially preventing one in five major cardiovascular events (e.g., heart attack or stroke) or premature deaths in this population. He noted that these important findings have implications for clinical guidelines for the care of people with HIV. Bill also observed that the findings are relevant to two of OAR’s signature programs: HIV and Aging, since the study population was people with HIV ages 40-75, and HIV and Women, since the results were equally applicable to women. View their conversation below:

IAS 2023, convening in Brisbane, Australia, features the latest advances in basic, clinical, and operational HIV research and seeks to move science into policy and practice. The conference features seven plenary sessions, more than 60 symposia and oral abstract sessions, hundreds of poster sessions, and many satellite sessions featuring highly diverse and cutting-edge research. Many of the studies that are being presented have been conducted by or funded by federal partners, including NIH, CDC, PEPFAR, DoD, and others.

As is the custom in Australia, HIV.gov acknowledges the Jagera and Turrbal people as the Traditional Custodians of Meanjin (Brisbane), the land on which IAS 2023 is taking place. We pay our respects to Jagera and Turrbal elders past, present, and emerging.

Follow all of our conversations from IAS 2023 this week here on the blog as well as on on HIV.gov’s Facebook, Instagram, and Twitter, and on the LinkedIn account of the HHS Office of Infectious Disease and HIV/AIDS Policy.

NIAID scientists and colleagues are one step closer to developing a safe and effective therapy against alphaviruses with the identification of SKT05, a monoclonal antibody (mAb) derived from macaques vaccinated with virus-like particles (VLPs) representing three encephalitic alphaviruses.

Spread by mosquitos, alphaviruses primarily affect people in one of two ways: causing severe neurological impairment such as encephalitis (brain swelling) or crippling muscle pain similar to arthritis. Western, eastern and Venezuelan equine encephalitis viruses (EEV) are examples of the former, while chikungunya and Ross River viruses are examples of the latter.

Building on studies from the past decade, scientists in NIAID’s Vaccine Research Center and colleagues knew that macaques produce dozens of different protective antibodies when experimentally vaccinated against the EEVs. In a new study published in Cell, the research team identified 109 mAbs in macaques immunized with the experimental western, eastern, and Venezuelan EEV VLP vaccine. All antibodies were individually tested for binding and neutralization against the three EEVs, with the best ones also assessed against arthritogenic alphaviruses not included in the vaccine. Collaborators included scientists from NIAID’s Laboratory of Viral Diseases, USAMRIID’s Virology Division, and Columbia University.

Their work identified SKT05 as the most broadly reactive antibody – remarkably, it also provided protection against both types of alphaviruses, those that cause encephalitis and those that cause arthritic-like disease. High-resolution structural studies further revealed that the way SKT05 binds to alphaviruses could make it resistant to surface changes that can occur in viruses – which means the mAb is likely to have lasting effectiveness.

Further studies are planned to investigate potential clinical development of SKT05. They aim to better define how SKT05 interacts with viruses and whether it can confer protective benefits against additional alphaviruses.

References:
M Sutton et al. Vaccine elicitation and structural basis for antibody protection against alphaviruses. Cell DOI: https://doi.org/10.1016/j.cell.2023.05.019 (2023).

EE Coates, et al. Safety and immunogenicity of a trivalent virus-like particle vaccine against western, eastern, and Venezuelan equine encephalitis viruses: a phase 1, open-label, dose-escalation, randomised clinical trial. Lancet Infectious Diseases (2022).

SY Ko, et al. A virus-like particle vaccine prevents equine encephalitis virus infection in nonhuman primates. Science Translational Medicine (2019).
 

Universal Influenza Candidate Vaccine Performs Well in Phase 1 Trial
mRNA Version of NIAID Vaccine Begins Similar Testing 

Scientists at NIAID’s Vaccine Research Center (VRC) report in two new studies that an experimental influenza vaccine, designed to elicit immunity against a broad range of influenza viruses, performed well in a small trial of volunteers. In fact, the vaccine has advanced to a second trial led by scientists at Duke University through NIAID’s Collaborative Influenza Vaccine Innovation Centers (CIVICs).

In a phase 1 clinical trial of 52 volunteers, the vaccine developed by the VRC – known as H1ssF (influenza H1 hemagglutinin stabilized stem ferritin nanoparticle vaccine) – was safe, well-tolerated, and induced broad antibody responses that target the hemagglutinin stem. The two new studies assessing the nanoparticle vaccine published April 19 in Science Translational Medicine.

Healthy volunteers ages 18-70 enrolled at the NIH’s Clinical Center and were given either a single 20-microgram dose or two 60-microgram vaccine doses. Boosters were given 16 weeks after the initial dose. The trial enrolled between April 1, 2019, and March 9, 2020. 

Trial participants did not experience any severe adverse events; the most common vaccine reactions included mild headache, tenderness at the vaccine site, and temporary general discomfort.

As anticipated based on preclinical study results, H1ssF generated binding antibodies to the stem of the influenza H1 hemagglutinin (HA) protein. Antibody responses were observed regardless of dose or participant age. “These responses were durable, with neutralizing antibodies observed over one year after vaccination,” the authors stated, suggesting this vaccine prototype can advance further universal influenza vaccine development.

The H1ssF vaccine using an mRNA delivery system also began testing in a phase 1 clinical trial being overseen by scientists at the Duke Human Vaccine Institute, a part of NIAID’s CIVICs network. 

HA is composed of head and stem domains and enables the influenza virus to attach and enter a human cell. The immune system can mount an immune response to HA, but most of the response is directed toward the head. Influenza vaccines must be updated each year because the HA head constantly changes – a phenomenon called “antigenic drift.” The new vaccine candidate consists only of the HA stem. The stem is more conserved than the head between influenza strains and subtypes, and thus is less likely to change every season. Scientists predict that targeting the HA stem without the distraction of the HA head could induce stronger and longer-lasting immunity.

Influenza A viral HA can be divided into groups 1 and 2, and further subdivided into multiple subtypes based on their sequences. Scientists used the stem of an HA from a group 1 influenza virus to create the nanoparticle vaccine. Both group 1 and group 2 influenza viruses are among those responsible for seasonal influenza as well as the sporadic and deadly outbreaks of avian influenza viruses with pandemic potential. The H1ssF vaccine elicited responses that broadly neutralized group 1 influenza A viruses. Additional clinical trials are underway to test a ferritin nanoparticle-based vaccine designed to elicit group 2 influenza A viruses, and to test the H1ssF and the group 2 vaccine together in a cocktail aimed at approaching universal influenza vaccine coverage.

The H1ssF vaccine is unique in that it only displays the stem part of the influenza HA protein on the surface of a nanoparticle made of nonhuman ferritin. Ferritin spontaneously self-assembles into an eight-sided nanoparticle. When designed to display a part of the HA protein, the ferritin-HA proteins form particles displaying HA spikes on their surface, mimicking the natural organization of HA on the influenza virus. Displaying influenza HA surface proteins on the outside of the nanoparticle makes them easily accessible to immune cells that encounter the nanoparticle. The immune system can then learn to develop antibodies against displayed proteins. 

References:
A Widge, et al. An Influenza Hemagglutinin Stem Nanoparticle 1 Vaccine Induces Cross
Group 1 Neutralizing Antibodies in Healthy Adults. Science Translational Medicine DOI: 10.1126/scitranslmed.ade4790 (2023).

S Andrews, et al. An Influenza H1 Hemagglutinin Stem-Only Immunogen Elicits a Broadly Cross-Reactive B Cell Response in Humans. Science Translational Medicine DOI: 10.1126/scitranslmed.ade4976 (2023).

ClinicalTrials.gov search identifier NCT03814720.