Lesson 9 — What Comes Next?
How Do Vaccines Actually Work?
Learning Material
1 pagesLesson 9 — What Comes Next?
Understanding the Complex: How Do Vaccines Actually Work?
The mRNA platform that produced COVID vaccines in eleven months did not emerge from nothing — it was built on decades of foundational research. But COVID did something else: it demonstrated, at scale, that the platform works. That demonstration changes the economics, the regulatory landscape, and the ambition of what vaccinologists are now willing to attempt.
The next decade of vaccine development may be more consequential than any since the mid-twentieth century.
HIV: the hardest target
HIV has killed roughly 40 million people since the epidemic began in the early 1980s. We have no vaccine. After more than forty years of effort, HIV remains one of the most formidable vaccination challenges in biology.
The difficulty is structural. HIV mutates rapidly — far faster than influenza — and it specifically attacks the cells of the adaptive immune system, the very system a vaccine must prime to work. The virus also establishes what is called a latent reservoir: it inserts itself into resting CD4+ T-cells, where it lies dormant, beyond the reach of either the immune system or antiretroviral drugs. Clearing that reservoir while preserving the cells that contain it is an unsolved problem.
mRNA approaches to HIV are now in early trials. Several candidates aim to produce broadly neutralizing antibodies — antibodies capable of neutralizing a wide range of HIV strains, not just the specific variant a person might encounter. Whether mRNA's flexibility and iterability will be sufficient to overcome the unique challenges of HIV remains genuinely uncertain.
Malaria: 600,000 deaths per year
Malaria kills approximately 600,000 people annually, the majority of them children in sub-Saharan Africa. The first approved malaria vaccine — RTS,S, developed by GSK over thirty years — received WHO recommendation in 2021 and is now being deployed. It offers roughly 30% efficacy against severe malaria in children, which in the context of the disease burden is clinically significant but not transformative.
A newer vaccine, R21/Matrix-M developed by the University of Oxford and manufactured by the Serum Institute of India, showed ~75–80% efficacy in Phase 2 trials in specific transmission contexts. It received regulatory approval in several countries in 2023.
mRNA-based malaria vaccines are in early development. The Plasmodium parasite — malaria's cause — is far more complex than a virus, with multiple life-cycle stages and thousands of proteins. Choosing which antigens to target is itself a significant research challenge. But the basic tools — rapid antigen design, iterative development, scalable manufacturing — are now available in a way they were not five years ago.
Universal flu vaccines
Seasonal influenza kills between 290,000 and 650,000 people globally each year. The annual flu vaccine works by targeting the specific strains predicted to circulate each season — a prediction that is sometimes right and sometimes not. The vaccine needs to be reformulated every year.
A universal influenza vaccine — one that would protect against all or most influenza strains, potentially for many years or life — has been a goal since the 1980s. It would require targeting parts of the influenza virus that remain constant across strains rather than the highly variable surface proteins that current vaccines target.
mRNA technology is particularly well suited to this challenge: because the sequence can be changed rapidly and manufactured quickly, it allows iterative approaches to finding conserved antigens and optimizing immune responses. Multiple Phase 1 and Phase 2 trials of mRNA universal flu vaccine candidates are underway.
Pandemic preparedness: how fast could we respond?
COVID demonstrated that the hard floor for mRNA vaccine development — design to clinical authorization — is approximately ten to twelve months when institutional barriers are removed and resources are unlimited. Could that be compressed further?
Several programs are now working to demonstrate a "100-day vaccine" — a vaccine ready for emergency use authorization within 100 days of a pandemic pathogen being sequenced. This is not science fiction; the sequencing of SARS-CoV-2 was available in January 2020, and a vaccine was in Phase 1 trials by March. The bottleneck was not design but authorization and manufacturing.
Pre-approved, pre-manufactured vaccine banks for likely pandemic strains — stockpiled against the possibility of antigenic shift in influenza, for example — represent another preparedness strategy. The challenge is that the right antigen to stockpile is, by definition, unknown until the pandemic strain emerges.
What is clear is that the world is better prepared for the next pandemic than it was for this one. Whether that preparation is sufficient remains to be seen.
Next lesson: What if...? — Three thought experiments at the frontier of what vaccines might become.
Reading time: approx. 9–10 minutes