For the past few years, SARS-CoV-2 and mRNA-based vaccines have dominated the scientific and clinical work on infectious diseases, but other diseases and vaccine approaches are attracting attention. For updates on some of the work underway, GEN reached out to experts at three vaccine-focused companies.
T-cell tactics
On April 21, 2022, a letter signed by dozens of infectious disease experts encouraged the U.S. Food and Drug Administration to keep T cells in mind when developing vaccines.1 Although this letter focused on treatments for COVID-19, T cells could be used to treat a variety of infectious diseases.
In the immune system, T cells complement antibodies. That is, both T cells and antibodies represent arms of the immune system. But in vaccine development, T cells have received relatively little attention.
“Vaccine development to date has really focused on antibodies,” affirms Andrew Allen, MD, PhD, CEO of Gritstone bio. Bucking this tendency, scientists at Gritstone bio develop vaccines for infectious diseases—and also cancer—by engaging both antibodies and T cells.
In general, the antibody arm is easier to strengthen than the T-cell arm. For example, Allen points out that making antibodies is easier than creating a robust response from killer T cells. He adds that antibody-based responses in blood are relatively easy to measure: “I just take some blood, and I can leave it on the shelf in the sunshine because antibody proteins are very stable. I can measure the antibody levels days later. Until very recently, the only way to measure antigen-specific T cells was to isolate live T cells from a blood draw very quickly, which most centers can’t do, and then the actual test itself is quite laborious, and you have to run lots of careful controls.”
Unsurprisingly, developers have tended to pursue antibody-based vaccines. But Allen is dissatisfied with a one-arm approach to infectious disease. “We ignore T cells even though we know that they matter,” he complains. “Our world ignores T cells for the sake of expediency, but our world is changing.”
Advanced approaches to T-cell-based vaccines
In Allen’s view, T cells will become more important in vaccine development largely through sheer necessity. Even if there is an antibody-based vaccine that can bind to the surface proteins of a virus, those proteins will change, which willl reduce the effectiveness of the vaccine. T cells can recognize any part of a virus.
“T cells often recognize highly conserved regions of a virus that don’t change frequently,” Allen says. “Therefore, in principle, you can get very good, durable protection that is against all of the variants of the virus, not just the one that’s in the original vaccine.”
Plus, today’s technology makes it easier to develop vaccines around T cells. For one thing, sequencing-based assays simplify measuring the resulting T cells with no need to separate them from the rest of the blood. For example, samples from people who have been infected and from people who haven’t can be analyzed to find patterns in their T-cell repertoires and variations in their human leukocyte antigen (HLA) systems.
“[That data is] complex, but this is where deep learning and mathematics come into action, because you need to pull data from different patients,” Allen says. “I have to learn from 5,000 people to start to see patterns associated with HLA and the disease phenotype.” The results can reveal who has good immunity to an infectious disease, who doesn’t, and how that information might be used to design an effective vaccine based on T cells.
“You want to build a vaccine that contains the T-cell targets in addition to B-cell targets, and that’s complicated because different people have different HLAs,” Allen explains. “So, it’s not a case of one-size-fits-all, because you may need to pick 10 different targets from within one gene region.”
In its work on cancer vaccines, Gritstone bio developed technology to find those targets. According to Allen, the technology allows the company to sequence the virus and then determine which bits of the virus seem to be conserved over time. Those bits of virus could serve as T-cell antigens.
“I put all of that together into a complex stew,” Allen continues. “And then I make a synthetic vaccine containing all these different T-cell antigen regions from the virus, which makes a vaccine vector that is capable of generating strong killer T cells.”
For COVID-19 and other infectious diseases such as influenza, Gritstone bio hopes to develop vaccines that provide broad and durable immunity comprised of T-cell and antibody responses. As Allen says, “If we can hit that, then this starts to become really interesting.”
Battling hepatitis B
Despite the availability of a vaccine against the hepatitis B virus (HBV), the pathogen continues to wreak havoc. According to the World Health Organization, HBV has infected about 254 million people and is killing more people every year.2 A large part of the danger is that “only 10 to 15% of all infected people are actually aware of their infection, because most of those people are living without any symptoms while the virus is still doing damage to the liver,” says Nadege Pelletier, PhD, chief scientific officer of Barinthus Biotherapeutics, which develops T-cell-based immunotherapies for chronic infections and autoimmune diseases. “Infected people can stay without any symptoms for up to 40 years, which means that they have time to transmit the disease without even knowing they have it.”
In addition, HBV has defense mechanisms to evade the immune system. For example, HBV produces high loads of hepatitis B surface antigen (HBsAg). “This antigen is actually a noninfectious particle,” Pelletier notes. “But this type of antigen acts as a decoy for the immune system, which means that it diverts the immune response to something irrelevant and will eventually lead to exhaustion of the T cells that are fighting it off. We end up with an immune system that just cannot take control over the disease.”
One current treatment approach for HBV involves chronic nucleotide analogs. “Although nucleotide analogs are quite well tolerated, only about 10% of the treated patients achieve functional cure,” Pelletier points out. “The other option is interferon, and that one is not very well tolerated. It has quite a lot of side effects that are frequently unbearable.”
Consequently, interferon treatments of HBV are usually short, too short to achieve a functional cure. So, many patients who receive interferon treatments of HBV will experience disease symptoms later in life, Pelletier observes. She adds that these symptoms can “go all the way to liver cirrhosis or development of hepatocellular carcinoma.”
According to Pelletier, the main reason existing treatments of HBV don’t achieve better rates of functional cure is their inability to target the underlying mechanism of the disease. “The disease is caused by a virus, but the pathology is not that of a very typical viral disease,” she explains. “The life cycle of the virus and all the evasion mechanisms that it puts in place—like all those decoys, including HBsAg—make chronic hepatitis B more an immunology disease than a viral disease, with HBV-specific T cells unable to control it.”
Pelletier and her colleagues believe that their vector-based immunotherapeutic candidate, VTP-300, can tackle the underlying pathomechanism of HBV. VTP-300 includes two vectors—an adenoviral vector and a modified vaccinia Ankara. Several viral antigens are encoded, and most HVB protein sequences are covered. “By injecting VTP-300, we reconstitute the pool of healthy HBV-specific T cells,” Pelletier says. That is, the pool regains HBV-specific T cells that are lost due to the disease. She adds that VTP-300 induces the production of HBV-specific T cells that are “polyfunctional and very potent against HBV-infected cells.”
Phase IIa and IIb trials are in progress in which patients are receiving two injections of VTP-300 in addition to nucleotide analog therapy. These trials have provided interim data showing that VTP-300—in combination with drugs such as PD-1 blockers or HBsAg-targeting siRNA—produces significant decreases in HBsAg.3 Indeed, in some patients, HBsAg reached undetectable levels, staying there long enough to suggest that these patients could end up with functional cures. Pelletier reports, “From a safety perspective, we haven’t seen anything unexpected or problematic.”
More than just managing mpox
Mpox—formerly known as monkeypox—can cause severe and life-threatening complications, particularly in children and pregnant women as well as in immunocompromised individuals.4,5 Like smallpox, mpox is caused by a virus from the orthopoxvirus family. These viruses pose a challenge for vaccine development because the multiple viral forms require the targeting of multiple viral proteins if protective immunity is to be achieved.
The global mpox outbreak, which was declared a public health emergency of international concern by the World Health Organization in 2022, demonstrated the urgent need for an effective, well-tolerated, and broadly available mpox vaccine. In response, BioNTech initiated an mRNA-based mpox vaccine program, BNT166. This vaccine program is in keeping with a statement that appears on the BioNTech website: “Regarding infectious diseases, BioNTech pioneers the development of mRNA vaccine candidates against tuberculosis, malaria, and human immunodeficiency virus as well as other infectious diseases with epidemic or pandemic potential, such as mpox.”
The BNT166 program encompasses multivalent vaccine candidates that encode surface antigens expressing the two infectious forms of the mpox virus. These vaccine candidates, which are designed to fight virus replication and infectivity, are being developed by BioNTech in partnership with the Coalition for Epidemic Preparedness Innovations (CEPI). Last year, BioNTech and CEPI announced that they are committed to enabling equitable access: “Any licensed vaccines developed as a result of this strategic partnership are expected to be made available at affordable prices in low- and middle-income countries.”
In a recent paper, BioNTech scientists reported that a multivalent mRNA monkeypox virus vaccine (BNT166) protects mice and macaques from orthopoxvirus disease.6 “These findings,” the scientists wrote, “support the clinical evaluation of BNT166 now underway (NCT05988203).”
From T cells to mRNA and beyond, companies will keep taking new approaches to treating and, it is hoped, even preventing many infectious diseases. As these diseases evolve, though, the work might never be done.
References
- Cross R. Scientists to FDA: Don’t forget about T cells. Boston Globe. April 22, 2022. Accessed September 5, 2024.
- World Health Organization. WHO sounds alarm on viral hepatitis infections claiming 3500 lives each day [news release]. April 9, 2024. Accessed September 5, 2024.
- Barinthus Biotherapeutics. Barinthus Bio’s VTP-300 Trials Demonstrate Ability to Achieve Undetectable HBsAg levels and Statistical Significance in Lowering HBsAg Levels in People with Chronic Hepatitis B [news release]. June 6, 2024. Accessed September 5, 2024.
- World Health Organization. Multi-country outbreak of mpox, External situation report#31. December 22, 2023. Accessed September 5, 2024.
- Centers for Disease Control and Prevention. Clinical Considerations for Mpox in People Who Are Pregnant or Breastfeeding. Updated June 11, 2024. Accessed September 5, 2024.
- Zuiani A, Dulberger CL, De Silva N, et al. A multivalent mRNA monkeypox virus vaccine (BNT166) protects mice and macaques from orthopoxvirus disease. Cell 2024; 187(6): 1363–1373.e12.