Roadmap for Vector Transmission Control (VTC)

What are we trying to achieve and why? What is the problem we are trying to solve?

To increase host resistance to vectors by elucidating protective adaptive immune responses and determining the vector antigens that provoke such responses.

What are the scientific and technological challenges (knowledge gaps needing to be addressed)?

• Identifying antigens (components) of vectors that induce protective adaptive immune response.
• For ticks, why is the homologue of BM86 (an antigen used as a protective vaccine) not transcribed in some individual ticks of the same species, and how does this impact vaccine efficacy?
• There is currently no standardized method for testing the efficacy of some anti-vector vaccines, which makes it difficult to compare results across studies. This lack of standardization also makes it difficult to determine which vaccines are most effective and thus a protocol needs to be established.
• Determining whether there is an efficient way to test whether a protective vector antigen is effective across a range of vector species. For example, could in vitro feeding of ticks with antibodies be used to demonstrate this?
• Determining whether vaccines are working better in 1-host ticks than 3-host ticks because of differences in feeding lengths. Again, could this be addressed by in vitro feeding systems?
• Evaluating which isotype (class) of antibody is needed to be induced in order for anti vector vaccines to be effective; that is, what effect does IgM, IgG, and IgE isotypes have?
• Developing anti-vector vaccines to affect all life stages of vector.
• Determining if an ongoing tick infestation at the time of vaccination affect vaccine efficacy.
• How effective are antibodies elicited by natural exposure to vector saliva in neutralizing functions of salivary proteins?
• What are the profiles of antibody responses of hosts elicited by exposure to vector salivary proteins during natural exposure and how do they interfere with vaccines against vectors based on these proteins (through antigen masking, antigen imprinting, inhibitory FcR signalling)?
• Determining which compounds ticks produce in their guts to protect themselves from vaccines, and how to overcome these protective mechanisms.
• Developing and testing vaccines for ticks can be challenging due to regulatory requirements and safety concerns. It can be difficult to obtain regulatory approval for new vaccines, which can slow down the development process. How can this be improved?
• Determining whether vaccinated animals rechallenged by natural exposure to the vector results in boosting the immune response. It seems immune animals don’t develop a memory response against the BM86 hidden antigens – is that true for all tick antigens? It has been proposed that T cells maintain memory a long time while B cells are more short-lived and thus does the BM86 vaccine only induce a T-independent B cell response?
• Why do Bos indicus (Zebu cattle) make more Abs to tick saliva proteins than taurine cattle?
• Can haemolymph antigens of the vector be used as vaccine candidates which would require transcytosis of antibodies through the gut?

What approaches could/should be taken to address the research question?

• Tick genomes could provide valuable insights into potential vaccine targets and thus it is necessary to continue to collect these.
• Determine which gut antigens are transcribed in various tick species through transcriptomic studies.
• Identify and target salivary antigens and other potential “cryptic antigens” beside gut antigens.
• Conduct long term trials to assess vaccine efficacy and duration of immunity.
• Use artificial feeding to determine the role of various Abs to kill the tick as well as to see which tick antigens are secreted.

What else needs to be done before we can solve this need?

• Vector saliva biochemistry: define the actual functions of molecules in saliva in a more systematic way using high throughput evaluation/screening of their functions particularly those affecting the host immune responses.
• Such knowledge also can feed into anti-vector drug discovery projects.
• Determining in general how the vector modulates the host immune system potentially preventing the host from developing a protective immune response.
• Need to know how many ticks an individual host can tolerate and still give a economically viable level of productivity and for the host to be considered to be in a state of well-being; that is, what level of reduction in infestation must a vaccine achieve for both of these aspects to be considered worthwhile.

Existing knowledge including successes and failures

• There is a current commercial vaccine for Rhicephalus (boophilus) microplus using the BM86 antigen. Studies are underway to evaluate its ability to induce cross-protection to other tick species.
• Vaccine trials that addressed the role of complement in immunity to tick-borne pathogens have shown contradictory results. One study published in the Journal of Immunology found that complement activation enhanced the immune response to tick-borne encephalitis virus, while another study in the Journal of Virology suggests that complement inhibition may be a useful strategy for improving vaccine efficacy against tick-borne diseases. These are apparently
  contradictory results that need to be clarified to determine their whether both are reproducible observations and if so, what is pathogen-specific reason for such differing outcomes.
• It is known that if the vector targets are so-called “hidden antigens” then there is a need for frequent boosters.
• RNA vaccination has been shown to induce tick resistance and pathogen transmission. (Sajid A, Matias J, Arora G, Kurokawa C, DePonte K, Tang X, Lynn G, Wu MJ, Pal U, Strank NO, Pardi N, Narasimhan S, Weissman D, Fikrig E. mRNA vaccination induces tick resistance and prevents transmission of the Lyme disease agent. Sci Transl Med. 2021 Nov 17;13(620) Epub 2021 Nov 17. PMID:34788080.)
• Ixodes scapularis saliva components that elicit responses associated with acquired tick-resistance (2020)
• A Vaccinomics Approach for the Identification of Tick Protective Antigens for the control of Ixodes ricinus and
• Dermacentor reticulatus infestations in companion animals (2019)
• New approaches and omics tools for mining of vaccine candidates against vector-borne diseases (2016)
• Transcription factors as a target for Vaccination against ticks and mites (2017)
• Phlebotomus papatasi exposure cross-protects mice against Leishmania major co-inoculated with Phlebotomus duboscqi salivary gland homogenate (2015)
• DNA plasmid coding for Phlebotomus sergenti salivary protein PsSP9, a member of the SP15 family of proteins, protects against Leishmania tropica (2019)
• Manning JE, Oliveira F, Coutinho-Abreu IV, Herbert S, Meneses C, Kamhawi S, Baus HA, Han A, Czajkowski L, Rosas LA, Cervantes-Medina A, Athota R, Reed S, Mateja A, Hunsberger S, James E, Pleguezuelos O, Stoloff G, Valenzuela JG, Memoli MJ. Safety and immunogenicity of a mosquito saliva peptide-based vaccine: a randomized, placebo-controlled, double-blind, phase 1 trial. Lancet. 2020 Jun 27;395(10242):1998-2007.
• Maruyama SR, Garcia GR, Teixeira FR, Brandão LG, Anderson JM, Ribeiro JMC, Valenzuela JG, Horackova J, Veríssimo CJ, Katiki LM, Banin TM, Zangirolamo AF, Gardinassi LG, Ferreira BR, de Miranda￾Santos IKF. Mining a differential sialotranscriptome of Rhipicephalus microplus guides antigen discovery to formulate a vaccine that reduces tick infestations. Parasite Vectors. 2017 Apr 26;10(1):206. Doi: 10.1186/s13071-017-2136-2
• David Odongo: used infected blood as a vaccine – no heterologous strain protection to Heartwater.