Chapter 141
Defeating Infectious Agents — 5
HIV affects 38 million people, with 1.3 million new infections in 2023. It’s resulted in over 600,000 deaths, and lifelong treatment with multiple antiretroviral drugs is required to keep the virus reservoir in check. Over forty years of dedicated effort has not yet delivered a vaccine. Why? HIV attacks and weakens the immune system, giving free rein for the virus to undergo extensive mutation in the body. The virus’s genome mutates at the highest rate known to science. Even in one person infected there can be one hundred thousand different strains of HIV, such that a vaccine would have to be effective at inducing neutralizing antibodies against most of these strains. A phase 1 trial of a vaccine of a nanoparticle containing sixty different copies of the HIV envelope protein induced broad neutralizing antibodies against HIV in 97 percent of forty-eight healthy people. Three different HIV mRNA vaccines are being assessed in healthy individuals for antibody production. mRNA nanoparticle vaccines directed to inducing precursor B cells have helped broaden the neutralizing antibody response in mice and nonhuman primates. These are early encouraging steps, but unfortunately, we’re still likely many years away from an HIV vaccine. In the meantime, clues from several people with HIV and leukemia who were cured with stem cell transplantation may lead to new approaches that obviate the need for transplants.
The mRNA nanoparticle platform is being applied to improve on traditional rabies vaccines, and is in clinical development for Zika virus, cytomegalovirus, herpes simplex virus, Epstein-Barr virus, Nipah virus, and chikungunya virus. That’s just a sample of what seems like a bottomless well of mRNA vaccines with applications beyond infectious disease protection. Cancer vaccines, genome editing, T cell engineering inside the body (in vivo), and tolerogenic vaccines for prevention of autoimmune diseases are or soon will be realities thanks to this medical technology.
STRENGTHS AND WEAKNESSES OF THE NEW VACCINES
Initially, the protection against SARS-CoV-2 infection, need for hospitalization, or death was extraordinary—about 95 percent—in the months following mass mRNA vaccination in 2021. Outside the United States, the other vaccine that became available early was an adenovirus platform (made by Astra Zeneca) in the UK, which was also very protective, at approximately 90 percent against severe disease. Breakthrough infections were quite rare, less than 1 percent. It had the look of a home run, maybe even a grand slam, flanked against prior vaccine programs.
But within six months, two things happened. First, the virus evolved into a variant named Delta with significant new mutations in the spike protein that made it more infectious and virulent compared with earlier strains of the virus (the ancestral Wuhan and Alpha). Second, there was waning of immunity with reduction of our neutralizing antibodies and immune response over time. A large placebo-controlled, randomized trial of a Pfizer/BioNTech third shot booster restored protection to 95 percent. The pattern of new variants followed by waning immunity followed by renewed vaccine boosters continued throughout the pandemic. By late 2021, the Omicron variant appeared with more than thirty new amino acid mutations and gathered momentum rapidly, dominating the globe, and the effectiveness of mRNA vaccines against infection plummeted. Vaccine protection against severe COVID remained strong, but even that fell and required successive boosters every six months.