How Is mRNA Technology Being Used to Develop an HIV Vaccine?
Despite these obstacles, hopes are now higher for a preventive HIV vaccine than ever before, both because so much more is now known about the virus, and because emerging vaccine platforms offer so many advantages over earlier approaches.
Indeed, the mRNA technology that has so far yielded two effective COVID-19 vaccines is being investigated for use against HIV—although none of these vaccine candidates have yet entered human vaccine trials for HIV. Preliminary results, however, are encouraging. One study found that immunization of humanized mice with low doses of LNP-encapsulated mRNA encoding the broadly neutralizing antibody (bNAb) VRC01 yielded high levels of protective HIV antibodies that may confer protection against HIV infection. The same research team subsequently showed that an LNP- encapsulated mRNA vaccine elicited strong cellular and humoral HIV immune response in rabbits and rhesus macaques, including T follicular helper cells that are thought to be critical to antigen-specific, durable B-cell responses.
The next step in mRNA vaccine technology, which may prove particularly important for mRNA vaccines against HIV, is the development of self- amplifying mRNA (saRNA). Derived from the genome of certain viruses, including alphaviruses and flaviviruses, saRNA expresses a viral replicase (Rep) that copies the mRNA into a complementary negative strand RNA, which Rep then uses to make more saRNA. At the same time, Rep uses a subgenomic promoter in the negative strand to produce smaller mRNA (subgenomic RNA) at levels 10 times higher than those of genomic RNA. This amplification leads to high production of antigen, which in turn generates a very strong immune response.
Another advantage of the LNP-encapsulated saRNA technology is that it produces a more durable expression of antigen than that obtained with mRNA. Experimental saRNA vaccines have produced cellular HIV immune responses in mice, and both cellular and humoral HIV immune responses in monkeys.
Kristie Bloom, Ph.D., a researcher in the antiviral gene therapy research unit at the University of the Witwatersrand in Johannesburg, South Africa, responded by email to questions about the promise of mRNA and saRNA technologies for both prophylactic and therapeutic HIV vaccine development. “The recent clinical achievements reported for the mRNA-based SARS-CoV-2 vaccine candidates highlight the potential of this technology and will help establish manufacturing and distribution platforms,” Bloom said. “The cell-free production and flexibility to adapt the mRNA transcript mean that novel HIV vaccines could be developed both to prevent and to treat HIV.
“Immunopotentiation from synthetic, self-amplifying RNAs may improve on current HIV mRNA vaccination strategies,” Bloom added. “However, first-in-human studies are still needed to confirm preclinical findings.”
How Is mRNA Technology Being Used to Develop an HIV Vaccine?
Despite these obstacles, hopes are now higher for a preventive HIV vaccine
than ever before, both because so much more is now known about the virus,
and because emerging vaccine platforms offer so many advantages over earlier approaches.
Indeed, the mRNA technology that has so far yielded two effective COVID-19
vaccines is being investigated for use against HIV—although none of these
vaccine candidates have yet entered human vaccine trials for HIV.
Preliminary results, however, are encouraging. One study found that
immunization of humanized mice with low doses of LNP-encapsulated mRNA
encoding the broadly neutralizing antibody (bNAb) VRC01 yielded high levels of protective HIV antibodies that may confer protection against HIV
infection. The same research team subsequently showed that an LNP-
encapsulated mRNA vaccine elicited strong cellular and humoral HIV immune
response in rabbits and rhesus macaques, including T follicular helper cells that are thought to be critical to antigen-specific, durable B-cell
responses.
The next step in mRNA vaccine technology, which may prove particularly
important for mRNA vaccines against HIV, is the development of self-
amplifying mRNA (saRNA). Derived from the genome of certain viruses,
including alphaviruses and flaviviruses, saRNA expresses a viral replicase (Rep) that copies the mRNA into a complementary negative strand RNA, which
Rep then uses to make more saRNA. At the same time, Rep uses a subgenomic
promoter in the negative strand to produce smaller mRNA (subgenomic RNA) at levels 10 times higher than those of genomic RNA. This amplification leads
to high production of antigen, which in turn generates a very strong immune response.
Another advantage of the LNP-encapsulated saRNA technology is that it
produces a more durable expression of antigen than that obtained with mRNA. Experimental saRNA vaccines have produced cellular HIV immune responses in
mice, and both cellular and humoral HIV immune responses in monkeys.
Kristie Bloom, Ph.D., a researcher in the antiviral gene therapy research
unit at the University of the Witwatersrand in Johannesburg, South Africa,
responded by email to questions about the promise of mRNA and saRNA
technologies for both prophylactic and therapeutic HIV vaccine development. “The recent clinical achievements reported for the mRNA-based SARS-CoV-2
vaccine candidates highlight the potential of this technology and will help establish manufacturing and distribution platforms,” Bloom said. “The cell-free production and flexibility to adapt the mRNA transcript mean that
novel HIV vaccines could be developed both to prevent and to treat HIV.
“Immunopotentiation from synthetic, self-amplifying RNAs may improve on
current HIV mRNA vaccination strategies,” Bloom added. “However, first-in-human studies are still needed to confirm preclinical findings.”