key: cord-292128-8o20mcur
authors: Fritschi, Nora; Curtis, Nigel; Ritz, Nicole
title: Bacille Calmette Guérin (BCG) and new TB vaccines: specific, cross-mycobacterial and off-target effects
date: 2020-08-20
journal: Paediatr Respir Rev
DOI: 10.1016/j.prrv.2020.08.004
sha: 
doc_id: 292128
cord_uid: 8o20mcur

The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG’s effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.

The reader will be able to 23 against other diseases. 23 In the following decades a reduction in all-cause mortality was 124 found in a number of controlled trials in the US, UK, Canada, India and Papua New Guinea, 125 and more recently in observational and randomised controlled studies mainly in Bissau. 24 A WHO commissioned systematic review, which analysed studies available up 127 until 2013, concluded that BCG reduced all-cause mortality by 30% (95% confidence 128 interval: −1% to 51%) in clinical trials. 25 Since then, two further randomised controlled trials 129 have been published. The first one, in Guinea-Bissau, showed a reduction in mortality in the 130 first 28 days of life by 30% (95% confidence interval: −6% to 53%), which decreased to 12% 131 at 6 and 12 months of age. 26 The second trial, done in intensive care units in India, showed 132 no significant change in reduction of mortality in the first 28 days of life of 5% (95% 133 confidence interval: −7% to 20%) in the BCG-immunised infants. 27 It has been proposed that 134 the difference in the results from Guinea-Bissau and India might be attributable to the use of 135 different vaccine strains (BCG-Denmark in Guinea-Bissau and BCG-Russia in India). 28 In 136 addition, the infants in India were of lower birth weight (< 2000 grams compared with < 2500 137 grams in Guinea-Bissau) and potentially sicker as they were in an intensive care unit. 138 139

The studies on reduction in infant mortality by BCG triggered studies on its protective effect 141 against respiratory tract infections, these being one of the most common causes of mortality 142 immunisation. 34 Similarly, for guardian-reported infections at 3-and 13-month telephone 177 interviews, there was no influence of BCG on the frequency of fever, pneumonia or cold 178 episodes. 35 Interestingly, in a post hoc subset analysis of infants whose mothers had received 179 BCG, there was a 32% (95% confidence interval: 1% to 54%) reduction in infections in the 180 first three months of life in the unadjusted hazard ration analysis 36 . A randomised study in 181

South African adolescents investigating a novel TB vaccine (H4:IC31) also included a BCG 182 revaccination arm. 37 Lower respiratory tract infections were rare in all groups over the 24 183 months follow-up period and there was no difference between BCG-revaccinated and non-184 revaccinated individuals. However, there was a reduction in upper respiratory tract infections 185 in BCG-immunised individuals compared with those who received the new TB vaccine or 186 placebo (2.1%, 9.4%, and 7.9% respectively). 187 188

Animal studies suggest that BCG has protective effects against viruses including influenza, 190 herpes simplex, hepatitis B and Japanese encephalitis. 18 Studies in humans that have 191 investigated prevention of viral diseases associated with BCG immunisation are rare. An 192 interesting randomised placebo-controlled study in 30 healthy male adults (not previously 193 BCG immunised) compared the immune response to a yellow fever immunisation as a "viral 194 challenge model" one month after BCG immunisation. 38 Viremia is usually detectable after 195 yellow fever immunisation in the first few days. The study showed a difference on day 5 after 196 yellow fever immunisation with higher viral loads in the non-BCG-immunised adults 197 compared to the BCG-immunised adults but this was not the case when viral loads were 198 compared on day 3 and 7. They also investigated in-vitro cytokine expression after BCG 199 immunisation and showed that with some stimulants and cytokines this was increased in the 200 BCG-immunised group. 38 Further, monocytes from BCG-immunised individuals responded 201 (transcriptionally) differently to a secondary in-vitro stimulus and suggesting that BCG-202 immunisation induces trained immunity in innate immune cells through epigenetic changes. 203 Innate immune responses have been shown to be important in both specific and off-target 204 effects of BCG. 39, 40 In the light of the evidence for off-target effects on viral respiratory tract 205 infections, it is therefore not surprising that BCG-immunisation has been proposed as a 206 potential prophylaxis against the novel severe acute respiratory syndrome coronavirus-2 207 (SARS-CoV-2). It is hypothesised that induction of a trained immunity by BCG 208 immunisation may reduce severity of coronavirus disease 2019 (COVID-19) and randomised 209 controlled trials are underway in several countries worldwide to assess whether BCG 210 immunisation reduces the incidence and severity of COVID-19 in healthcare workers. 19,41 211 However, although BCG immunisation is generally safe in children and adults, it is also 212 possible that up-regulation of innate immunity by BCG immunisation will exacerbate 213 COVID-19 and therefore BCG immunisation for COVID-19 should only be given within 214 clinical trials. 41,42 Cautious interpretation is also needed for pre-publication released 215 ecological studies suggesting that countries with longstanding and universal BCG 216 immunisation policy have reduced mortality and numbers of COVID-19 cases. 43, 44 . Such 217 ecological studies are prone to significant bias from many confounders, including differences 218 in national demographics and disease burden, different definitions used for COVID-19 219 (confirmed cases only versus inclusion of presumed cases), testing rates for SARS-CoV-2, 220 and the stage of the pandemic in each country. 43, 45 In addition, the current expert opinion is 221 that BCG vaccine given many years earlier is unlikely to protect against COVID-19 as 222 trained immunity induced by BCG might not be long-lasting and is likely abrogated by other 223 vaccines. 46 These and several other ecological studies should therefore be interpreted with 224 caution as BCG is -including during the COVID-19 pandemic -essential for the prevention 225 of TB in infants and young children. It therefore should not be used for the prevention of 226 COVID-19 before solid evidence for its effectiveness for this indication is available. 47 

Today the BCG vaccine is universally administered as an intradermal injection, but the 316 original BCG was given orally. In Brazil, the BCG-Moreau strain was used as an oral vaccine 317 until 1976. 75 In addition, animals studies done almost 50 years ago, showed superior 318 protection when intravenous and aerosol application were used compared with intradermal 319 administration. 76 Recent data from a study in macaques compared TB prevention after 320 intradermal, intravenous and aerosol BCG immunisation (given via a paediatric mask 321 attached to a Pari eFlow nebuliser). 77 The study had a complex design with several BCG 322 administration routes: low-dose and high-dose intradermal, intravenous, aerosol and a 323 combination of aerosol and intradermal. To compare the effects of intravenous and 324 intradermal administration, only the high-dose intradermal and the intravenous groups should 325 be compared as these received 5 x 10 7 colony forming units (CFU) of BCG-Denmark. 326

Intravenous BCG administration resulted in a higher frequency of specific CD4 and CD8 T 327 cells in blood and parenchymal lung tissue compared with the two other routes of 328 immunisation. After the challenge with M. tuberculosis Erdman 6 to 10 months after BCG 329 immunisation, macaques that had received intravenous BCG showed superior protection The vaccine is also being tested in trials in several other settings in adults for prevention of 443 disease and recurrence, and also for its off-target effects on bladder cancer. 83 

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Figure 1: Summary of the specific, cross-mycobacterial and off-target effects of BCG relevant to children 754

Only vaccines that are in (or 757 registered for) phase II or III trials are included. The colours around vaccines denote trials 758 that have shown improved protection (green), no improvement (orange)

H4:IC31: fusion protein of antigens 85B and TB10.4 with IC31 adjuvant 762 H56:IC31: fusion protein of antigens 85B, ESAT-6 and Rv2660c with IC31 adjuvant

M72/AS01E: fusion protein of antigen 32A and 39A with AS01E adjuvant 764 MVA85: modified vaccinia Ankara 85A

TB/FLU-04L: influenza A vectored vaccine expressing the antigens 85A and ESAT-6

MTBVAC: live attenuated M. tuberculosis strain (Euro-American lineage 4) with deletion mutations in the 767 virulence genes phoP and fadD26 768 VPM1002C: live attenduated M. bovis BCG-Prague (rBCGΔureC:Hly)

DAR-901: heat-killed, fragmented M. tuberculosis cultured under stress conditions 770 MIP: heat-killed Mycobacterium indicus pranii a non-pathogenic, non-tuberculous mycobacterium approved in 771 India as a leprosy vaccine

heat-killed Mycobacterium vaccae a non-pathogenic, non-tuberculous mycobacterium