Research roadmap for contagious bovine pleuropneumonia (CBPP) vaccine development

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Vaccine

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Dependencies

2 Naturally attenuated candidates
2A Safety
2B Delivery route
2C Delivery platform
2D Efficacy in challenge model
3 Rationally attenuated candidates
3A Safety
3B Delivery route
3C Delivery platform
3D Efficacy in challenge model
4 Inactivated vaccines
4A Safety
4B Delivery route
4C Delivery platform
4D Efficacy in challenge model
5 DNA/RNA vaccines
5A Safety
5B Delivery route
5C Delivery platform
5D Efficacy in challenge model
6 Subunit vaccines
6A Safety
6B Delivery route
6C Delivery platform
6D Efficacy in challenge model
7 Vectored vaccines
7A Safety
7B Delivery route
7C Delivery platform
7D Efficacy in challenge model

Vaccine

Research Question

Use existing live attenuated vaccines (LAVs) to control CBPP caused by Mycoplasma mycoides (Mmm) in Africa to improve cattle productivity and gain access to new markets.
1. Could better implementation of current LAVs (T1/44 or T1sr) help bring CBPP under control?
Is it possible to develop more efficacious and safer vaccines than the current LAVs

Research Gaps and Challenges

Better diagnostic tools of the different clinical phases of CBPP are needed to support LAVs vaccination campaigns.
Issues such as need for a cold chain, short duration of immunity after a single LAV dose, the incidence of side effects, access to vaccine, diluent composition, short shelf life after reconstitution and policies restrict the routine use of current LAVs.
No new attenuated vaccines which improve on the LAVs developed in the 1950s.
No inactivated or subunit commercial vaccines have been developed.
Incomplete knowledge on acquired and innate immune responses that mediate or contribute to immunity and to disease.
Incomplete knowledge on subunit antigens associated with immunity or those that contribute to disease.
Cattle breed, age and health status influence immunity and huge differences can occur between individuals in response to infection.
Lack of in vitro tests that correlate/associate with different clinical manifestations of and immunity to CBPP.
Currently, the only way to assess vaccine improvements is via laboratory or field challenge trials.
Field trials to assess vaccine efficacy are not ideal in early phase vaccine R&D.
Difficulty in obtaining sequential data from natural outbreaks because of long and variable incubation periods.

Solution Routes

Resolve conflicting data on the quality, safety, use and efficacy of existing LAVs.
Establish if there is a dose response in cattle breeds between route of immunization and interval between primary and booster vaccinations to obtain the best safety, efficacy and duration of immunity in different age groups of cattle using existing LAVs.
Standardize cattle breed specific laboratory challenge models that reproduce CBPP caused by natural infection or are acceptable surrogates of natural infection.
Develop disease related metrics that do not rely on postmortem data to assess vaccine efficacy.
Determine the impact of different clinical phases of CBPP on the epidemiology of disease.
Develop assays and biomarkers for improved diagnosis of disease and immunity to CBPP.
Use assays and biomarkers to guide and design improved use of LAVs, new generation vaccines and diagnostic tests, including DIVA vaccines.
Develop an antigen map of Mmm through different phases of CBPP and stages of disease.
Explore the protective capacity of candidate vaccine antigens using different vaccine platforms.

Dependencies

Develop community agreed minimum and optimal vaccine TPPs to prioritize and guide vaccine R&D.
Harmonize regional, national, and continental wide vaccination policies and campaigns for better manufacture and delivery of LAVs.
Improve fragmented veterinary services and vaccine supply chain.
Incentivize use of GMP and AU-PANVAC certified LAV vaccines.
Assess vaccine effectiveness and implement pharmacovigilance in disease control.
Attract animal health companies to help deploy LAVs and develop new generation vaccines.

State Of the Art

Epidemiological data show that CBPP continues to spread within sub-Saharan Africa, with some reports suggesting that Mmm may also be circulating in parts of Asia.
The incubation period for naturally infected animals can range from 3 weeks to 6 months with clinical manifestations ranging from hyperacute through acute, subacute and persistence of chronic forms after the clinical phase.
The disease is mainly localized in the lungs, where it causes a highly characteristic “marbling” of the lungs in the acute stages and lesions known as a “sequestra” that contain viable Mmm in the chronic form of CBPP.
Mmm is transmitted by close contact between animals within 50m.
The role of sequestra in transmission remains controversial.
The immune response to experimental infection differs when challenged by different routes such as intubation or by contact.
Despite genotypic and phenotypic differences between Mmm strains, they all appear to fall into a single immunity group.
Most countries eliminated CBPP by adopting integrated control strategies, e.g., biosecurity measures, control of animal movement, vaccination, diagnosis, slaughter and compensation.
Animals that develop sequestra have significantly higher antibody titres against Mmm surface proteins than those that did not.
Due to the weak economies in Africa, control of CBPP via restricting cattle movement, slaughter and compensation are not suitable options.
The attenuated Mmm strains T1/44 and T1sr are recommended by WOAH for vaccination.
LAVs are given either sub-cutaneous in the neck (T1sr) or the tip of the tail (T1/44).
Side effects are only associated with T1/44, but their incidence decreases on boosting, or by including skimmed milk in the vaccine during freeze drying.
Vaccine efficacy of LAVs ranges from ~40-60% and increases on boosting.
T1/44 is more efficacious than T1sr.
Duration of immunity with T1/44 is 1 year and for T1sr, 6 months.
Control by vaccination alone requires >80% vaccine coverage and booster doses.
Elimination of disease with current LAVs will need booster vaccination and removal of infected cattle.
It is estimated that only 16% of the vaccine required to vaccinate 80% of Africa’s 370 million at-risk cattle population was produced in 2022.
Mycoplasma specific IgA is present in bronchoalveolar lavage (BAL) and the sera of less severely affected cattle, and antiserum from convalescent animals induce mycoplasma killing by macrophages.
There is no correlation between antibody titres and severity of clinical disease and lesions.
Attempts to vaccinate with immunogenic purified proteins may lead to disease exacerbation suggesting a type III hypersensitivity reaction leading to damage by immune complexes.
Higher levels of IFN-g in convalescent and fully recovered animals suggested that cell mediated immunity (CMI) plays a role in the immune response to CBPP, though differences in the CMI between cattle with and without lesions have yet to be seen in experimental and natural infections.
Bovine respiratory explants have been developed to help understand the early immune events. These show that Mmm preferentially attaches to the lower respiratory tract, is cytotype specific and can locate inside non-phagocytic cells. Furthermore, the pathogen shows a higher tropism to the ciliated bronchial epithelial cells leading to ciliostasis and tissue destruction within 24 hours.
Simple and inexpensive changes to the current vaccine, such as the use of HEPES buffer systems and the inclusion of pH indicators together with restrictions in the use of 1 M MgSO4 as a vaccine diluent, can increase vaccine yields 10-fold and stability several 100-fold, producing a vaccine which should improve its effectiveness in the field.
Antibody dependent growth inhibition assays can be used in diagnosis.
There are encouraging results on the development of a subunit vaccine using a combination of four Mmm antigens.