Denise Monack of Stanford University in the U.S. will use a genetic approach to identify the molecular mechanisms that enable the typhoid fever-causing bacterium S. Typhi to survive in aquatic environments and to rapidly adapt to transmission to humans. Annually, S. Typhi causes over 20 million infections and 200,000 deaths, mostly among populations that lack access to clean drinking water. Understanding how S. Typhi persists in water and then quickly adapts to its human host is critical for controlling transmission. Bacteria use various mechanisms to adapt to environmental changes, including so-called RNA thermometers (RNATs), which form secondary structures in mRNAs that can rapidly activate gene expression when temperatures change. They will use their established genetic screening approach to identify new RNATs in S. Typhi and validate their ability to promote bacterial persistence within aquatic microbial communities by generating mutants. They will also follow up on past work in which a bioinformatics approach identified new RNATs that may regulate the expression of the chitinase enzyme, which is used by the cholera-causing bacterium to bind to plankton and create a protective environmental niche. They will evaluate whether chitin is also important for S. Typhi persistence and transmission.

The current vaccine against bacterial pneumonia (pneumococcus) requires a regimen of four injections given at specific intervals. In developing countries, this not only complicates the vaccination process for health workers and children, but it also is a serious obstacle for families who must travel long distances to the nearest health clinic. Dr. Curtiss and his colleagues are working to develop new vaccines against bacterial pneumonia that require only a single dose, can be delivered orally, and are safe for newborns, infants, and people who are malnourished or whose immune systems are compromised.

Pietro Alano of the Instituto Superiore de Sanità in Italy will develop a biochip that mimics the midgut of the Anopheles mosquito and can be used to more easily and quickly test candidate anti-malarial compounds for blocking transmission of the causative Plasmodium parasite. Malaria is a potentially fatal infection caused by parasites transmitted between humans through the bites of infected mosquitoes. When a mosquito bites an infected person, immature Plasmodium gametocytes enter the mosquito and transform into an invasive ookinete stage in its midgut. They then traverse the gut wall to the external gut lumen, where they enter their parasite stage. To eliminate malaria, compounds are needed that block the transmission of Plasmodium. However, current methods to evaluate the candidate transmission-blocking drugs or vaccines that are under development are slow and involve feeding malaria-infected blood to mosquitoes, which is potentially dangerous. As an alternative, they will create a biochip to reproduce the mosquito midgut environment that can support the development of parasites, and develop a bioluminescent antibody-based technique to count successfully traversing ookinetes. They will test the performance of the biochip using known anti-transmission drugs.

Dr. Yoshihiro Kawaoka of the University of Tokyo in Japan will develop broadly effective influenza vaccines by mixing together epitopes of conserved fragments of the viral hemagglutinin (HA) protein, which only elicit a weak immune response, together with millions of different, non-naturally occurring fragments that elicit a strong immune response, to induce broadly cross-reacting antibodies. Influenza is of world-wide concern severely impacting public health and the global economy. Tens of millions of reported cases result in tens of thousands of deaths annually in the U.S. alone, and the rapid spread of the virus between countries causes epidemic or pandemic outbreaks. Traditional vaccines are directed towards selected epitopes in the head region of the viral HA protein because they elicit a strong immune response. However, these regions are frequently mutated, rendering the vaccines useless. Vaccines directed towards more conserved epitopes only elicit a weak immune response, but this can be strengthened using HA proteins previously unseen by the immune system. They will produce a library of millions of HA epitopes that contain artificial mutations in the immune-dominant regions while preserving the conserved regions. This should focus the production of highly reactive antibodies against the conserved HA epitopes, which will eliminate a wider range of influenza strains. They will test this using single and repeat immunizations of different mixes in ferrets. Once optimized, the vaccination strategy will be tested in ferrets pre-exposed to influenza virus to mimic the human situation. The result will be a single vaccination that protects against a wider range of influenza strains than traditional vaccines.