applied sciences Review Update on TB Vaccine Pipeline Carlos Martin 1,2,3,* , Nacho Aguilo 1,2, Dessislava Marinova 1,2 and Jesus Gonzalo-Asensio 1,2 1 Grupo de Genética de Micobacterias, Microbiología, Facultad de Medicina Universidad de Zaragoza, 50009 Zaragoza, Spain; [email protected] (N.A.); [email protected] (D.M.); [email protected] (J.G.-A.) 2 CIBERES Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain 3 Servicio de Microbiología, Hospital Universitario Miguel Servet, 3ISS Aragón, 50009 Zaragoza, Spain * Correspondence: [email protected] Received: 10 March 2020; Accepted: 31 March 2020; Published: 10 April 2020 Abstract: In addition to antibiotics, vaccination is considered among the most efficacious methods in the control and the potential eradication of infectious diseases. New safe and effective vaccines against tuberculosis (TB) could be a very important tool and are called to play a significant role in the fight against TB resistant to antimicrobials. Despite the extended use of the current TB vaccine Bacillus Calmette-Guérin (BCG), TB continues to be transmitted actively and continues to be one of the 10 most important causes of death in the world. In the last 20 years, different TB vaccines have entered clinical trials. In this paper, we review the current use of BCG and the diversity of vaccines in clinical trials and their possible indications. New TB vaccines capable of protecting against respiratory forms of the disease caused by sensitive or resistant Mycobacterium tuberculosis strains would be extremely useful tools helping to prevent the emergence of multi-drug resistance. Keywords: BCG; tuberculosis vaccines; TBVI; EDCTP; IAVI; CTVD 1. Introduction To date, vaccines have been able to overcome the evolution of antibiotic-resistant strains, which makes vaccination one of the most cost-effective measures for fighting infectious diseases [1]. Mycobacterium tuberculosis (Mtb) is included as ‘critical’ in the WHO priority list of research and development for new antibiotics effective against current resistant strains of tuberculosis (TB) [2]. Concurrently, new efficacious vaccines will be a very important tool to fight antimicrobial resistant TB (AMR TB) and are called to play an important role against this serious health issue [1]. The potential of using TB vaccines to combat AMR TB has generally been undervalued. This could be partly due to the lack of integral efficacy of the present vaccine Bacillus Calmette-Guérin (BCG) failing to reduce the numbers of TB cases, which makes new efficacious vaccines against respiratory forms of TB a critical necessity to help combat AMR TB. Currently, one of the biggest threats in TB is the emergence of multidrug-resistant (MDR) Mtb strains, resistant to isoniazide and rifampicin, and extensively drug-resistant (XDR) strains, resistant to at least four of the core anti-TB drugs. In 2018, half a million people were diagnosed with MDR-TB and is estimated that fifty million people were infected with MDR Mtb strains, creating a reservoir for future cases of active TB making treatment extremely difficult [2]. AMR poses a threat in TB; both the World Health Organization (WHO) and International Centres for Disease Control and Prevention (CDC) have expressed concern about antibiotic treatments for TB. New TB vaccines are necessary to complement existing and in-development pipeline TB treatment and diagnostic strategies. Considering there has been no evidence to suggest that molecular mechanisms of drug resistance in Mtb could affect immune control susceptibility, it is likely that vaccine efficacy against MDR-TB and drug-sensitive TB will be equivalent [3]. In the present work we review the current use of BCG and the non-specific effect against other pathogens and we summarized the diversity of new TB vaccine candidates in clinical trials and Appl. Sci. 2020, 10, 2632; doi:10.3390/app10072632 www.mdpi.com/journal/applsci Appl. Sci. 2020, 10, x FOR PEER REVIEW 2 of 15 Appl. Sci. 2020, 10, 2632 2 of 15 indications. We discuss the need to keep the pipeline of new TB vaccine candidates and the current clinicaltheir indications. trial designs We employed discuss the in need the field to keep for theefficacy pipeline determination of new TB vaccineof new candidatesTB vaccines and which the includecurrent clinicaldesigns trial for designsprevention employed of infection in the field(POI), for prevention efficacy determination of disease (POD), of new and TB vaccines prevention which of recurrenceinclude designs of TB for(POR), prevention or trials offor infection evaluating (POI), the therapeutic prevention ofeffect disease of TB (POD), vaccine and candidates prevention when of appliedrecurrence in combination of TB (POR), with or trials current for evaluatingTB drug regimens the therapeutic with the eaimffect to of shorten TB vaccine duration candidates of treatment. when Theapplied pipeline in combination includes new with prime current TB TB vaccines drug regimens for administration with the aim at to shortenbirth, which duration are ofexpected treatment. to protect better than BCG, and for use in adolescents and adults, as revaccination strategies in The pipeline includes new prime TB vaccines for administration at birth, which are expected to protect individuals previously vaccinated with BCG at birth, as per WHO Preferred Product Characteristics better than BCG, and for use in adolescents and adults, as revaccination strategies in individuals (PPC) for new TB vaccines [3,4]. Novel TB vaccine strategies, which are safe and effective, are previously vaccinated with BCG at birth, as per WHO Preferred Product Characteristics (PPC) for new imperative in the global efforts to halt dissemination of drug-sensitive and AMR TB [3]. TB vaccines [3,4]. Novel TB vaccine strategies, which are safe and effective, are imperative in the global efforts to halt dissemination of drug-sensitive and AMR TB [3]. 2. BCG the Current TB vaccine in Use 2. BCGDespite the Current its variable TB Vaccine efficacy in against Use respiratory forms of TB, BCG remains the only marketed vaccineDespite in use its against variable TB, e ffiwithcacy more against than respiratory 90% coverage forms in ofcountries TB, BCG with remains high theTB incidence only marketed [5–7] vaccine(Figure 1). in useBCG against is an attenuated TB, with morevaccine than derived 90% coverage from Mycobacterium in countries bovis with, the high etiologic TB incidence agent of [5 –TB7] (Figurein cattle1 ).[8]. BCG BCG is was an attenuated first introduced vaccine in derivedclinic almost from aMycobacterium hundred years bovis ago,, thewhen etiologic in 1921 agent it was of TBadministered in cattle [8 ].orally BCG to was a baby first whose introduced mother in had clinic died almost of TB a the hundred day after years her ago, birth. when The inbaby 1921 showed it was noadministered adverse effects orally to to BCG a baby vaccination whose mother and, more had died importantly, of TB the daydid afternot develop her birth. TB. The Between baby showed 1921 and no 1926adverse more eff ectsthan to 50,000 BCG vaccination children were and, vaccinated. more importantly, Mortality did notamong develop vaccinated TB. Between children 1921 was and 1.8%, 1926 comparedmore than 50,000to a mortality children weregreater vaccinated. than 25% Mortality in unvaccinated among vaccinated children, childrenshowing was its effectiveness 1.8%, compared in reducingto a mortality infant greater mortality, than 25%not only in unvaccinated due to TB if children,not due to showing other respiratory its effectiveness diseases in reducing [9]. Today infant we knowmortality, that not the only main due cause to TB of if attenuation not due to otherof BCG respiratory is due to diseases the loss [ 9of]. Region Today we of knowDifference that the 1 (RD1) main associatedcause of attenuation with the loss of BCG of the is due virulence to the lossfactor of Regionof the secreted of Difference immunodominant 1 (RD1) associated antigen with of the 6 kDa loss (ESAT-6)of the virulence [8]. factor of the secreted immunodominant antigen of 6 kDa (ESAT-6) [8]. Figure 1. Bacillus Calmette-Guérin Calmette-Guérin ( (BCG)BCG) vaccination vaccination coverage coverage by by country. Data Data from from the the World Health Organization about the BCG coverage in each country [[10,11].10,11]. A total of of 113 113 countries countries reported reported coverage of at least 90%90%. [[2].2]. In 1976, WHO established the Expanded ProgramProgram on Immunization (EPI) to ensure universaluniversal access ofof mothers mothers and and infants infants/children/children to routinely to routinely recommended recommended infant/ childhoodinfant/childhood vaccines. vaccines. Initially, Initially,there were there six vaccine-preventable were six vaccine-preventable diseases included diseases in the included EPI: TB, poliomyelitis,in the EPI: diphtheria,TB, poliomyelitis, tetanus, pertussisdiphtheria, and tetanus, measles. pertussis Intradermal and measles. vaccination Intradermal with BCG vaccination at birth has with been BCG included at birth in thehas WHO been includedEPI, resulting in the in WHO more thanEPI, fourresulting billion in vaccinesmore than administered four billion worldwide vaccines administered to date and approximatelyworldwide to date200 million and approximately doses given each 200 year.million Depending doses given on strain each andyear. manufacturer Depending ofon BCG, strain concentration and manufacturer of live ofbacteria BCG, inconcentration vaccine vials of can live range