Just 12 months after the first cases of COVID-19 were identified, two vaccines have received emergency use authorization in the U.S. and are already being deployed around the world, with more vaccines on the way. By stark contrast, after 30 years of scientific and clinical research, there’s still no vaccine for HIV, prompting the question: Will the new technologies that produced COVID-19 vaccines push us that much closer to an HIV vaccine?
The first two COVID-19 vaccines to enter clinical use are both examples of messenger RNA (mRNA) vaccines with lipid nanoparticle (LNP) delivery systems. The first vaccine, BNT162, is manufactured by Pfizer in partnership with the German biotechnology company BioNTech. The second, mRNA-1273, is manufactured by Moderna, a biotechnology company based in Cambridge, Massachusetts. The use of the mRNA platform catapulted these vaccine candidates from the laboratory into clinical trials and now into clinical practice.-
What Is mRNA Technology, and How Is It Used in Vaccine Development?
The major vaccine types include whole-pathogen vaccines, subunit vaccines, and nucleic acid vaccines. Nucleic acid vaccines are the most recent innovation; they include plasmid DNA vaccines and mRNA vaccines. Each approach uses genetic material that encodes one or more antigenic proteins. Upon vaccination, the genetic payload enters the cytosol, or liquid matrix, of human cells, where the cellular machinery uses the genetic material to produce antigens that elicit an immune response.
As vaccine platforms, nucleic acid technologies have a number of distinct advantages over older approaches:
- They are fast and easy to manufacture.
- The encoded immunogenic proteins do not remain in the human body for very long.
- The immune system amplifies the genetic material in response even to small amounts of the expressed antigenic protein.
When nucleic acid vaccine platforms were first pioneered in the 1990s, researchers were more sanguine about plasmid DNA than they were about mRNA. This hesitancy around mRNA was due to perceived problems regarding its stability and immunogenicity, or ability to produce an immune response.
The primary hitch was that mRNA is rapidly degraded in the human body by nucleic enzymes called RNases. Thus, upon injection, the mRNA might never even make it to the antigen-presenting cells in a quantity sufficient to elicit the desired immune response. The other major issue was that mRNA is itself an immunologically active molecule, and introducing mRNA into the immune system might stimulate excessive immune activation that could lead to dangerous levels of inflammation.
Taken together, the instability and excessive immunogenicity of mRNA discouraged researchers from exploring mRNA vaccine platforms and contributed to the relative enthusiasm for plasmid DNA technologies.
The turning point for mRNA vaccine development came in the mid-2000s at the University of Pennsylvania, where Hungarian biochemist Katalin Karikó, Ph.D., and colleagues demonstrated that the use of modified nucleosides made mRNA that was transcribed in vitro more stable and less immunogenic. Karikó is today the senior vice president at BioNTech, the biotech company that partnered with Pfizer in developing BNT162, the COVID-19 vaccine that has since become the first mRNA vaccine to complete phase 3 clinical trials, receive authorization for clinical use, and be used to vaccinate human beings. (To date, no DNA plasmid vaccine has been approved for use in humans).
Another critical aspect of mRNA vaccine technology is the delivery system—the method used to protect the mRNA from degradation and facilitate uptake into human cells. A number of such delivery systems have been explored, including covalent conjugates, protamine complexes, nanoparticles based on lipids or polymers, and hybrid formulations using one or more of these approaches. Of these options, the most promising have been lipid nanoparticles (LNPs), which provide not only improved antigen stability and immunogenicity, but also targeted delivery and slow release. The Pfizer/BioNTech and Moderna vaccines both use LNP encapsulation as their delivery mechanism.
After 30 Years, an HIV Vaccine Remains Elusive
In a recent interview in the American Journal of Managed Care, Anthony Fauci, M.D., the director of the National Institute of Allergy and Infectious Diseases, was asked to compare the challenge of developing a COVID-19 vaccine with that of developing an HIV vaccine. Fauci said that his confidence in developing an effective COVID-19 vaccine was based largely on the fact that the human body mounts an effective immune response against natural infection with SARS-CoV-2, the virus that causes COVID-19.
This is emphatically not the case with HIV, Fauci explained. “It is very difficult to get a vaccine [for HIV], because it’s very difficult to induce the body to do something that even natural infection doesn’t successfully allow it to do, [which] is to develop an adequate immune response to clear the virus,” he said. “The challenges are very, very different.”
A number of factors contribute to the so-far insurmountable difficulty of developing a preventive vaccine for HIV. The tremendous genetic diversity of HIV is first on the list. Amino acid sequences of the HIV Env protein can differ up to 20% between viruses within a particular clade and as much as 35% in virus samples from different clades. Any successful immunogen would have to elicit broadly neutralizing antibodies against several HIV strains, and that has proven difficult to achieve.
Next, HIV establishes latent viral reservoirs early in the course of infection, complicating the task of the immune system.
Another major challenge is the lack of clear correlates of immunity. Vaccines generally work by reproducing the innate human immune response to a pathogen. Since the human immune system cannot eradicate HIV, we are left in the dark about what factors constitute an effective immune response (although ongoing research continues to narrow this knowledge gap). In addition, HIV is adept at evading both humoral and cellular immune responses. Moreover, an attenuated virus would be unsafe for human use, thus rendering many conventional vaccine approaches out of the question for HIV.
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.”