Chapter 139
Defeating Infectious Agents — 3
One other powerful catalyst of the mRNA breakthroughs was Operation Warp Speed. The idea for this program came from Peter Marks, a senior FDA physician-scientist and Trekkie. A public-private partnership was officially announced in May 2020, funded initially with $10 billion, to accelerate clinical trials, and de-risk mass production of candidate vaccines. That means they would be mass-produced and discarded if the vaccine didn’t work in clinical trials, at no cost to the company that manufactured them. The overarching goal, not lacking any boldness, was to produce and deliver three hundred million doses of safe and effective vaccines by January 2021. Pfizer was not included in the group of companies that were subsidized at “warp speed” but did receive an advance government purchase order in July 2020 for $2 billion. It has been estimated that Operation Warp Speed itself saved the lives of 140,000 Americans.
Billions of doses of mRNA COVID vaccines have since been administered to people throughout the world, which has propelled the mRNA/lipid nanoparticle vaccine platform for most infectious diseases, a partial group shown in figure 10.2.
The respiratory syncytial virus program exemplifies the recent extraordinary progress that has been made in vaccines, not relying on mRNA. First identified as a pathogen in 1956, it took sixty-seven years to get a vaccine approved. For context on how desperately one was needed, about 120,000 children die from this virus each year; more than half of these are infants under six months of age. In older adults, in the United States, respiratory syncytial virus accounts for about one hundred thousand hospitalizations, and eight thousand deaths occur each year.
In 2023, the results from four randomized, placebo-controlled clinical trials of three different vaccines were reported. All were single dose with marked efficacy, up to 94 percent protection in people aged sixty and older and 82 percent when given to pregnant women, protecting their babies from RSV out to six months. This remarkable achievement emerged from a rational, structure-based design of a vaccine. Defining the atomic structure of the prefusion protein enabled, ultimately, a powerful immune response in the individual. Again, it is the same winning strategy used for the COVID vaccines, manipulating the spike protein with the 2-proline substitution. Besides the vaccine for protection against respiratory syncytial virus, the first single-dose monoclonal antibody (nirsevimab, Beyfortus) to prevent this virus for newborns and babies was FDA approved in 2023. It, too, is an outgrowth of knowing the prefusion structure, since the antibody binding locks the protein in a prefusion formation, unable to get into cells.
Annual flu shots have limited effectiveness that can vary to as low as 20 percent when there is a mismatch of the flu strain anticipated to that which actually circulates months later. The influenza virus has two main types, A and B, and twenty subtypes; the vaccine primarily targets the surface hemagglutinin (see fig. 10.2), but the virus mutates at a lively rate, and this hampers the vaccine’s effectiveness. Imprinting, also known as original antigenic sin, occurs whereby our exposure to preexisting strains of the virus, and the memory B cells that are generated, reduces protection to new circulating strains. Our immune response tends to get stuck on our first exposure to a pathogen, not having the agility to react as adeptly and specifically to a new strain. “Sin,” original or not, is perhaps not the best word researchers might have come up with.