Human brucellosis: recent advances and future challenges

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Brucellosis control
In endemic areas, control of brucellosis is the first challenge. The only way to control human brucellosis is to control the animal disease and stop passage to man. Brucellosis has been controlled or even eradicated in a small number of wealthy countries, by long and costly programs of animal vaccination followed culling of infected animals at later stages. Food hygiene, especially pasteurization of milk is of great importance to prevent human infections. Excellent reviews by JM Blasco [1,2] discus this in detail.
Control of a disease such as brucellosis requires a 'One Health' approach. Animal and human health must work together with the livestock holders and programs established inform and educate the population at risk. Strong implication of political decision makers is essential.
If not yet established, surveillance of human and animal populations should be implemented.
Vaccination programs need good vaccines. Two live vaccines, B. melitensis Rev. 1 and B. abortus S19 have been used over past decades with great success for, respectively, small ruminant and bovine brucellosis control programs throughout the world. B. abortus RB51 is also proposed as a vaccine for bovine brucellosis to be used in the final stages of control programs in conjunction with test and slaughter. None of the available vaccines are perfect; they cause abortion in target and non-target animals, can be shed by immunized animals and all can cause brucellosis in humans. RB51 is also resistant to rifampicin, one of the drugs of choice to treat human brucellosis. We need new effective vaccines that are safe for both animals and humans. There are many projects aiming to improve the efficiency and safety of existing vaccines and to develop new vaccines. There is currently an international call for development of a new brucellosis vaccine with a substantial prize for the first new vaccine licensed (https://brucellosisvaccine.org/). Here, the focus is on a vaccine that will be beneficial in endemic regions. In past years, work has been strongly oriented to vaccines, and diagnostic tools to solve problems in countries with low levels of incidence (generally rich countries in the later stages of control programs). This has led to the DIVA concept (distinguishing between infected and vaccinated animals). While not relevant in a country with high prevalence and no infrastructure to test animals [2], DIVA compliance would make a vaccine more attractive in rich countries and therefore more commercially viable for the manufacturer. The general methods to create a DIVA vaccine have been to remove an immunogenic antigen from the vaccine (such as the loss of O-antigen in RB51). This may reduce efficiency of the vaccine (hence the attempts to restore O-antigen production to RB51 [3]) and mean that accidental human infections are not detected [4]. A more efficient method could be to express an unrelated immunogenic protein in the vaccine strain that would induce a detectable serological response not seen in infected animals. This approach has used for viral vaccines for some time [5] and has recently been used with S19 by the Moreno group in Costa Rica [6].

Strain identification and molecular epidemiology
MALDI-TOF mass spectrometry is revolutionizing the clinical diagnostic laboratory, but not all machines can identify Brucella. We developed a spectral database allowing Brucella to be identified by the bioMérieux VITEK system [7] and a safe, rapid protocol for solvent inactivation before analysis. Solvent inactivated bacteria are stable for several days, allowing transport to a centre with a machine [8].
Multilocus sequence typing (MLST) and Multiple-Locus Variable number tandem repeat Analysis (MLVA) is now used throughout the world for molecular epidemiology. These studies are showing how B. melitensis and B. abortus strains have been transported across the world by animal trade and will be important in the future control programs [9,10]. The advances in sequencing technology will lead to the generalisation and automatization of in silico core genome MLST and MLVA analysis using whole genome sequences.

Scientific Integrity
The final challenge is not scientific. An increasing number of cases where scientific integrity was not respected. While some may be unintentional, others include data falsification, image manipulation and plagiarism. Scientific advancement is built on the foundations of solid published data. 'Fake Science' is as dangerous as 'Fake News'. It is our responsibility to ensure that all published papers in the field are honest.
I hope that this thematic series of Infectious Diseases of Poverty: Control strategy and case management of human brucellosis, will be the opportunity to report scientific advances in our understanding of brucellosis and describe how they are helping us control this disease.