Stabilizing the malaria vaccine protein

Scala’s technology enables heat-stable, low-cost malaria vaccine protein to allow widespread use

Why it matters

Vaccines intended for widespread use in regions with unreliable electricity and limited cold‑chain infrastructure must be produced in tens of millions of doses and remain stable without refrigeration. Scala’s computational stability design strengthens fragile protein subunits by improving their folds from structure and sequence in a single round.

RH5 is one example: stability beyond 50°C, manufacturable in bacteria, with immune features preserved, all are required for an affordable vaccine. The same approach shows how unstable proteins can be transformed into robust, manufacturable vaccine candidates, pointing to broader opportunities wherever stability is a barrier to development.

Problem

The RH5 antigen was a strong malaria vaccine candidate but collapsed near 40 °C and could be produced only in insect cells. These limits drove up cost and forced cold-chain storage, which is hard to maintain across long transport routes with unreliable electricity. Without improved stability and a lower-cost host, RH5 could not progress as a practical vaccine.

What was done

A single round of stability design generated three RH5 variants with 15–25 mutations each.

All variants were tested for bacterial expression, thermal stability, and immune-relevant properties compared to wild-type. The goal was to enable robust folding and manufacturability while keeping the immune surfaces intact.

Results

• Thermal stability: +10–15 °C vs baseline

• Expression host: insect cells → E. coli

• Variants: 3 designs, 15–25 mutations each

• Efficacy: retained ligand binding and immune-relevant properties equivalent to wild type

• Development note: the stabilized RH5 variant was advanced as a vaccine candidate suitable for use in infants and young children

Impact

By removing cold-chain dependence and shifting to high-yield bacterial expression, the stabilized RH5 variant overcame two major bottlenecks that had blocked affordable development.

This demonstrates the value of Scala's stability design platform in vaccine development enabling proteins that are both manufacturable and fit for their intended use, with direct implications for global health.

Data highlights

• Expression: Wild-type RH5 showed no detectable bacterial expression.

  All three variants expressed at high levels under matched conditions:

  
  

  

  
  

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• Thermostability: The lead variant increased apparent melting temperature

  by 10–15°C relative to baseline:

  
  

  

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• Immune features: Stabilized RH5 retained binding and immune-relevant

  properties equivalent to wild type:

  
  

  

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References

Campeotto I., Goldenzweig A., Davey J., Barfod L., Marshall J. M., Silk S. E., Wright K. E., Draper S. J., Higgins M. K., and Fleishman S. J. (2017). One-step design of a stable variant of the malaria invasion protein RH5 for use as a vaccine immunogen. PNAS 114(5). https://doi.org/10.1073/pnas.1616903114

*King, L. D. W.; Pulido, D.; Barrett, J. R.; Davies, H.; Quinkert, D.; Lias, A. M.; Silk, S. E.; Pattinson, D. J.; Diouf, A.; Williams, B. G.; McHugh, K.; Rodrigues, A.; Rigby, C. A.; Strazza, V.; Suurbaar, J.; Rees-Spear, C.; Dabbs, R. A.; Ishizuka, A. S.; Zhou, Y.; Gupta, G.; Jin, J.; Li, Y.; Carnrot, C.; Minassian, A. M.; Campeotto, I.; Fleishman, S. J.; Noe, A. R.; MacGill, R. S.; King, C. R.; Birkett, A. J.; Soisson, L. A.; Long, C. A.; Miura, K.; Ashfield, R.; Skinner, K.; Howarth, M. R.; Biswas, S.; Draper, S. J. (2024) Preclinical Development of a Stabilized RH5 Virus-like Particle Vaccine That Induces Improved Antimalarial Antibodies. Cell Rep. Med. 5(7). https://doi.org/10.1016/j.xcrm.2024.101654