RTS,S/AS01 – Spells “How to Save Lives”

Welcome back. In the last malaria podcast, we covered the background and challenges malaria presented regarding vaccines. Today, we will lightly touch upon some of the intricacies of Mosquirix, the first-ever vaccine against the disease. You may also know this vaccine by the catchy name RTS,S/AS01. Can hardly imagine why anyone would want to label it with a tradename like Mosquirix.

RTS,S also presents itself as an excellent opportunity to cover some commonly used terms in veterinary vaccinology: recombinant, chimeric, humoral, cell-mediated, prime-boost, and adjuvant. It furthermore challenges the myth that only modified live vaccines promote cell-mediated immunity.

If you prefer to listen to podcasts, feel free to play the audio version of this blog by clicking on the player above.

Podcast: RTS, S/AS01 Spells "How to Save Lives:" Malaria Vaccine Part 2
Length: 6 minutes 10 seconds
Written and read by the author

The four letters of RTSS refer to the four different proteins that have been cut and pieced together. Occasionally, we refer to this as a chimeric compound. In mythology, a chimera had the body of a goat, a head of a lion and the tail of a serpent. Apropos with how different the RTS,S proteins are.

The R provides a humoral or antibody response, the T stands for T-cell which implies cell-mediated, the first S is for a completely different pathogen, namely Hepatitis B, and the last S is a free S binding protein that helps everything come together. Truly a chimera.

While some vaccines utilize the entire pathogen, either live or dead, others just focus on a piece or pieces of it. To build the protein pieces, you can take the DNA coding that you have identified for the protein you want, splice the genetic material together, and insert into a cell. The cell culture then makes the protein in the laboratory for you. In this case, researchers use yeast. This is one method for recombinant technology.

In general, we think of vaccines stimulating the system to make antibodies which confer protection. Free-floating antibodies come from the branch of the immune system we call Humoral Immunity and is one of two branches of the adaptive system. The “R” piece of the vaccine represents an antibody binding site on the invading Plasmodium organism. Ideally, the vaccine creates antibodies which bind and help neutralize the pathogen before they can migrate to the liver.

Since Plasmodium is crafty, the concern would be that some organisms might make it through to the liver and burrow inside the cells. Once inside, they are protected from the free-floating antibodies. Thus, the other branch of the immune system is necessary.

The “T” stands for T-cell, and this antigen stimulates the other branch of the immune system that we call Cell Mediated. Once a cell becomes invaded by a pathogen, the cell expresses a protein unique to the parasite in hopes to alert the immune system. By vaccinating the system with the T protein, Cytotoxic T cells can quickly recognize the infected liver cells and stop the malarial replication.

Cell-mediated vaccines present challenges to make, and several methods are being pursued. One is called Prime-Boost, which utilizes another related vaccine given before the RTS,S vaccine series. Providing a Hepatitis B vaccine before the malaria vaccine appears to show some results but not enough to warrant use of this protocol. The current strategy will be a series of four RTS,S vaccines. Still, prime boost remains a method that is occasionally used in human medicine.

The adjuvant system, AS01, has shown benefits towards stimulating the cell-mediated system. Non-adjuvanted RTS,S and various adjuvanted options with the vaccines have been tried. To date, the AS01 provides the best efficacy. AS01 is a liposome formulation of MPL and QS21. Sounds like a mouthful but bear with me. A liposome is basically an oil bubble with water inside. The water holds both MPL and QS21. MPL stands for Monophosphoryl Lipid A, a type of adjuvant currently being studied for anti-cancer vaccines and QS21 derives from the bark of a Chilean tree.

What matters is that this combination of a recombinant, conglomerate protein with the AS01 adjuvant promotes better humoral and cell-mediated immunity than other combinations and vaccines tried so far.

1. Cluff CW. Monophosphoryl Lipid A (MPL) as an Adjuvant for Anti-Cancer Vaccines: Clinical Results. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7284/
2. Leroux-Roels, G., Leroux-Roels, I., Clement, F., Ofori-Anyinam, O., Lievens, M., Jongert, E., … Cohen, J. (2014). Evaluation of the immune response to RTS,S/AS01 and RTS,S/AS02 adjuvanted vaccines: randomized, double-blind study in malaria-naïve adults. Human vaccines & immunotherapeutics, 10(8), 2211–2219. doi:10.4161/hv.29375
3. Ockenhouse, C. F., Regules, J., Tosh, D., Cowden, J., Kathcart, A., Cummings, J., … Vekemans, J. (2015). Ad35.CS.01-RTS,S/AS01 Heterologous Prime Boost Vaccine Efficacy against Sporozoite Challenge in Healthy Malaria-Naïve Adults. PloS one, 10(7), e0131571. doi:10.1371/journal.pone.0131571
4. Ouédraogo, A., Tiono, A. B., Kargougou, D., Yaro, J. B., Ouédraogo, E., Kaboré, Y., … Sirima, S. B. (2013). A phase 1b randomized, controlled, double-blinded dosage-escalation trial to evaluate the safety, reactogenicity and immunogenicity of an adenovirus type 35 based circumsporozoite malaria vaccine in Burkinabe healthy adults 18 to 45 years of age. PloS one, 8(11), e78679. doi:10.1371/journal.pone.0078679
5. World Health Organization. (2018, August 24). Q&A on the Phase 3 trial results for malaria vaccine RTS,S/AS01. Retrieved May 12, 2019, from https://www.who.int/malaria/media/rtss-phase-3-trial-qa/en/#What were the vaccine efficacy trial results?
6. Zhu, D., & Tuo, W. (2015). QS-21: A Potent Vaccine Adjuvant. Natural products chemistry & research, 3(4), e113. doi:10.4172/2329-6836.1000e113

[amazon_link asins='1118553985,1935660020,0199946647,130526892X,1607951789' template='ProductCarousel' store='vetzone-20' marketplace='US' link_id='aa3e86be-ce1c-11e7-ae16-0944a45c35a3']