Oxford TB vaccine study calls into question selective use of animal data
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.j5845 (Published 10 January 2018) Cite this as: BMJ 2018;360:j5845
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In reply to the letter from Dr. Cunningham, we provide the following safety data from the MVA85A infant efficacy trial, which were posted on clinicaltrials.gov in 2013 when the trial was published:
The seven (1%) deaths in the vaccine group included two from kwashiorkor, two from non-tuberculous meningitis, one from gastroenteritis, one from asphyxia due to drowning, and one from sudden death; and the four (<1%) in the placebo group included two from gastro enteritis, one from encephalitis, and one from a lower-respiratory-tract infection (Tameris M et al, The Lancet 2013). These death rates were not significantly different and reflect the known infant mortality in this setting. Of the two cases of tuberculous meningitis, one was in the placebo group and the other, which was subsequently reclassified as viral meningitis, was in the MVA85A group.
Helen McShane, The Jenner Institute, University of Oxford
Adrian Hill, The Jenner Institute, University of Oxford
Mark Hatherill, South African Tuberculosis Vaccine Initiative, University of Cape Town
Michele Tameris, South African Tuberculosis Vaccine Initiative, University of Cape Town
Jacqui Shea, Aeras
Ann Ginsberg, Aeras
Competing interests: Helen McShane: I am supported by a diverse group of funders, including the Wellcome Trust, The Bill and Melinda Gates Foundation, Aeras and the European Commission, to develop new TB vaccines. MVA85A was developed in my laboratory. Adrian Hill: I am Director of the Jenner Institute, where MVA85A was developed, and have received grant income from a large number of funders for vaccine development, especially against malaria. I am a co-inventor of several vaccine technologies licensed through Oxford University Innovations. Mark Hatherill: I have received support through institutional grants to the University of Cape Town from multiple funders including Aeras and Wellcome Trust for clinical trials of several TB vaccine candidates including MVA85A. Michele Tameris: I have worked on multiple TB vaccine projects funded by Aeras and Wellcome Trust including MVA85A projects. In addition I have previously received two Wellcome Trust International Engagement grants. Jacqui Shea: I was the general manager of the Oxford Emergent TB Consortium, the commercial licensor of the MVA858A vaccine and part funder of the MVA85A trial. I am currently CEO of Aeras, one of the funders and sponsor of the MVA85A trial. Ann Ginsberg: I am currently the Chief Medical Officer for Aeras. Aeras was one of the funders and sponsor of the MVA85A trial.
Deborah Cohen suggests, based on animal studies, that it was unethical to test MVA85A in infants (BMJ 2018;360:j5845). She said nothing about the results of the South African trial (Tameris, McShane, et al. Lancet 2013;381:1081) so I read the study myself, mainly looking for adverse events. The summary stated, “…the numbers of infants with serious adverse events (257—18%--and 258—18%--) did not differ between groups.” The authors concluded that, “MVA85A was well tolerated…” The text reveals that 7 infants died in the vaccine group and 4 infants died in the placebo group; it also mentions 2 cases of tuberculous meningitis but does not state which groups they came from. May we have that information from Professor McShane?
I have not studied this systematically, but have the distinct impression that vaccines are commonly licensed in the face of serious safety concerns, especially pertaining to Kawasaki disease. Some of the vaccines in question and relevant trials include: influenza (Walter, Ped IDJ 2009;28:1099. Nolan, JAMA 2010;303:37), rotavirus (FDA Notice 6/15/07. Hua, PedIDJ 2009;28:943. CDC, “Kawasaki syndrome and RotaTeq vaccine” 3/23/10), pneumococcal conjugate (Center, PedIDJ 2009;28:438. Tseng, Vaccine 2013;31:2578), and meningococcal B (Gossger, JAMA 2012;307:573. Vesikari, Lancet 2013;381:8250).
There seem to be at least two techniques used to dismiss safety concerns in order to get a vaccine licensed. First, adverse events are arbitrarily dismissed as “biologically implausible”, or “unrelated to the vaccine.”…Second, adverse events are dismissed because the association is not statistically significant.
RotaTeq was associated with a 5-fold risk of Kawasaki disease (P=0.10) in a licensing trial (CDC 2010). This signal was ultimately dismissed using VAERS for “postmarketing surveillance” (Hua 2009), but it was never acknowledged that fewer than one in 200 KD cases in the US are ever reported to VAERS. (Cunningham, “Fever, convulsions, vaccines, and Kawasaki disease .” BMJ rapid response 6/11/10. “Underreporting vaccine adverse events.” BMJ rr 7/16/10). A similar sequence of events occurred with Prevnar 7 and Prevnar 13 (Center 2009. Tseng 2013). So far, I’ve seen no postmarketing data on Bexsero.
Heplisav-B was recently licensed in spite of a 7-fold risk increase for myocardial infarction (chi-square=4.80, P=0.028 by my calculation), possibly because of the inflammatory effects of the new adjuvant (Packer, medpagetoday.com 11/14/17). It will be interesting to see how Dynavax manages postmarketing surveillance of their vaccine.
I hope we can see the numbers from the MVA85A infant trial. Maybe they will be OK, but saying that, “the vaccine was well tolerated” is not enough.
Allan S. Cunningham, January 18, 2018
Competing interests: No competing interests
[The delay in posting this response was due to an oversight at the journal]
The article by Deborah Cohen raises questions for me.
Apparently Oxford University, Professor McShane and other investigators in the clinical trial in South Africa have financial interests in MVA85A. In this day, can it ever be appropriate for financially conflicted individuals and organisations to have senior roles in design, interpretation and reporting of clinical studies on their product?
The authors' declaration in their Lancet article seems to be less than full.[1] Professor Adrian Hill is listed as a member of the study team but his role is not stated. Cohen reported that he owned shares but that is not mentioned in the conflicts of interest section of the paper.[1] I find it surprising that the magnitude of financial conflicts of interest are not stated.
Can we be told whether the investigators fully declared their financial interests in the vaccine when applying for funding, ethics approval, and informed consent from parents?
Reference
1. Tameris MD, Hatherill M, Landry BS, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised placebo-controlled phase 2b trial. Lancet 2013;381:1021-8.
Competing interests: No competing interests
A study performed at the Health Protection Agency [HPA], now Public Health England [PHE], has been highlighted in a feature about vaccine research and the role of pre-clinical studies in the BMJ. PHE has responded to all requests for information about this study, but in the interest of clarity and transparency in animal research we would like to make the following comments.
1. Animal studies at HPA/PHE are conducted to extremely high standards , and they were and continue to be compliant with the UK Animals (Scientific Procedures) Act 1986 and the EU Directive 2010/63/EU. The study in question was designed and conducted in accordance with these regulations, and the aims and all experimental details of the study are openly stated in the 2010 publication.1 Any suggestion that this TB model development study was conducted as a preclinical trial to support the progression of vaccine MVA85A in to human trials is incorrect.
2. On page 2 of the BMJ article, it is stated that: ‘… although the difference between the BCG and MVA85A groups wasn’t statistically significant, the Porton Down study gave a strong signal that the MVA85A vaccine was hastening the development of TB in the macaques, raising the possibility that MVA85A was actually impairing the effectiveness of BCG.’
There was no evidence from any read-out used in the study to support the claim that the MVA85A vaccinated group developed progressive disease more rapidly. As outlined in the original publication1, the HPA study was the first attempt to develop a new model for vaccine assessment using aerosol challenge. Our work was published after careful analysis of all study parameters and without any delay once analyses had been concluded on material from the macaque study, and this was completed during 2009. Whilst the use of survival was unable to discriminate outcome among the groups, the pulmonary disease burden was shown to be significantly reduced in animals vaccinated with BCG alone, or BCG boosted with MVA85A, compared to the unvaccinated control group when measured by a new and more sensitive read-out of disease using advanced imaging.1 It should be noted that in the years following completion of this initial exploratory study, further refinements to the design of the macaque model have been introduced.
Reference:
1Sharpe SA, H McShane, MJ Dennis, R J Basaraba, F Gleeson, G Hall, A McIntyre, K Gooch, S Clark, N E R Beveridge, E. Nuth, A White, A Marriott, S Dowall, AVS Hill, A Williams, & PD Marsh (2010). Establishment of an aerosol challenge model of tuberculosis in rhesus macaques, and an evaluation of endpoints for vaccine testing. Clinical & Vaccine Immunology;17(8):1170-82.
M W Carroll
Competing interests: No competing interests
The article by Cohen[1] questions the justification for a large efficacy trial of the novel tuberculosis (TB) vaccine MVA85A in South African infants[2]. This trial, completed in 2012, confirmed that the vaccine candidate was safe and the data collected provided valuable insights to the TB vaccine research field[3]. While we strongly agree with calls for rigor in conducting, and openness in reporting, preclinical studies, we are confident that moving forward with this efficacy trial was justified. Unfortunately, Cohen’s article fails to distinguish between a lengthy academic disagreement and scientific misconduct.
Buried within the misleading eight-page narrative are three key points:
• There had been 14 clinical trials of MVA85A in over 400 humans (the target species) before the infant efficacy trial. None showed a safety signal. When the University of Cape Town human research ethics committee reviewed the patient information sheet, they judged that the emphasis on human, rather than animal data was appropriate for their approval process.
• Cohen and Beverley persistently imply that data in a non-human primate (NHP) experiment (Sharpe et al) were misrepresented. However, we specifically drew the attention of the regulators to this study and gave them the raw data, as soon as the full dataset was available, eight months before the start of enrolment in the infant trial. They explicitly made the judgement that the results were insufficient to reverse their decision to approve.
• Three separate panels, appointed by Oxford, conducted investigations triggered by Beverley’s complaints, all of which found no evidence of wrong-doing.
Progressing this vaccine to a major field efficacy trial involved the judgement of many people in multiple organisations in several countries. The ultimate measure of those judgements is that the vaccine was found to be safe and advanced the field of vaccination against TB, the world’s leading infectious disease killer. These trial results were published immediately, within 10 working days of our first seeing the data[2,4].
We agree that there is still much important progress to be made in developing more predictive animal models, especially in the field of TB vaccine research. And we cannot make progress without testing new vaccines in humans. Importantly, the MVA85A vaccine was designed to protect through induction of very high T cell responses. Humans show better T cell responses after MVA85A vaccination than animals because we are extensively exposed to, and primed by, environmental mycobacteria, which express the same antigen 85A ]5]. Therefore, this type of vaccine could be more protective in humans than in animal models. This provided a much larger part of the rationale to assess MVA85A in a human efficacy trial than the animal data discussed by Beverley and Cohen.
Beverley’s complaints and the Cohen article fail to cite the positive efficacy demonstrated by a BCG-MVA85A regime in the then standard intra-tracheal challenge model undertaken by a leading Dutch group[6] – the only non-human primate study to evaluate MVA85A in an established challenge model. Indeed, their very selective citation here appears quite different to the policy that the BMJ claims to be encouraging.
The meta-analysis cited[7] combined data from limited numbers of animal studies conducted in four different species, testing different regimes and doses with varying effectiveness, and with three different endpoints. Given the heterogeneity in animal models for TB vaccine evaluation, this flawed approach misses the point that the different conditions and models were seeking to identify a preferred regimen with clear efficacy, not to calculate the average effect across all regimens and models.
We re-emphasize that the main driver for testing the efficacy of MVA85A was the excellent human safety and T cell immunogenicity, which was significantly higher than that induced by any other new candidate vaccine at that time, and seen across 14 clinical trials conducted over seven years in over 400 adults and children in three countries.
To reiterate: we are strongly supportive of calls for greater rigour in conducting, and openness in reporting, pre-clinical findings in vaccinology. However, Cohen fails to recognise the exceptionally thorough reporting of pre-clinical findings on MVA85A and the extensive safety data provided by previous human trials, which justified moving into the phase 2 clinical trial in infants. The MVA85A programme observed the highest scientific and ethical standards, aiming to improve global control of the world’s most lethal infectious disease.
Helen McShane, The Jenner Institute, University of Oxford
Adrian Hill, The Jenner Institute, University of Oxford
Mark Hatherill, South African Tuberculosis Vaccine Initiative, University of Cape Town
Michele Tameris, South African Tuberculosis Vaccine Initiative, University of Cape Town
Jacqui Shea, Aeras
Ann Ginsberg, Aeras
References
1. Cohen D. Oxford vaccine study highlights pick and mix approach to preclinical research. BMJ 2018;360:j5845 doi: 10.1136/bmj.j5845
2. Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, Shea JE, McClain JB, Hussey GD, Hanekom WA, Mahomed H, McShane H; MVA85A 020 Trial Study Team. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet. 2013 Mar 23;381(9871):1021-8.
3. Fletcher HA, Snowden MA, Landry B, Rida W, Satti I, Harris SA, Matsumiya M, Tanner R, O’Shea MK, Dheenadhayalan V, Bogardus L, Stockdale L, Marsay L, Chomka A, Harrington-Kandt R, Manjaly Thomas ZR, Naranbhai V, Stylianou E, Darboe F, Penn Nicholson A, Nemes E, Hatherill M, Hussey G, Mahomed H, Tameris M, McClain JB, Evans TG, Hanekom WA, Scriba TJ, McShane H. T-cell activation is an immune correlate of risk in BCG vaccinated infants. Nat Commun. 2016 Apr 12;7:11290.
4. McShane HT, M; Landry, BS; Snowden, MA; Lockhart, S; Scriba TJ; Mahomed, H; Hatherill, M. BMJ 2014;348:g3058.
5. McShane H, Pathan AA, Sander CR, Keating SM, Gilbert SC, Huygen K, Fletcher HA, Hill AV. Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG primed and naturally acquired anti-mycobacterial immunity in humans. Nat Med 2004 Nov;10(11):1240-4.
6. Verreck FA, Vergennes RAW, Kondova I, van Kralingen KW, Remarque EJ, Braskamp G, van der Werff NM, Kersbergen A, Ottenhoff THM, Heidt PJ, Gilbert SC, Gicquel B, Hill AV, Martin C, McShane H, Thomas AW. MVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaques. PLoS One. 2009; 4(4):e5264.
7. Kashangura R, Sena ES, Young T, Garner P. Effects of MVA85A vaccine on tuberculosis challenge in animals: systematic review. Int J Epidemiol 2015, Sep 8. pii: dyv142.
Competing interests: Helen McShane: I am supported by a diverse group of funders, including the Wellcome Trust, The Bill and Melinda Gates Foundation, Aeras and the European Commission, to develop new TB vaccines. MVA85A was developed in my laboratory. Adrian Hill: I am Director of the Jenner Institute, where MVA85A was developed, and have received grant income from a large number of funders for vaccine development, especially against malaria. I am a co-inventor of several vaccine technologies licensed through Oxford University Innovations. Mark Hatherill: I have received support through institutional grants to the University of Cape Town from multiple funders including Aeras and Wellcome Trust for clinical trials of several TB vaccine candidates including MVA85A. Michele Tameris: I have worked on multiple TB vaccine projects funded by Aeras and Wellcome Trust including MVA85A projects. In addition I have previously received two Wellcome Trust International Engagement grants. Jacqui Shea: I was the general manager of the Oxford Emergent TB Consortium, the commercial licensor of the MVA858A vaccine and part funder of the MVA85A trial. I am currently CEO of Aeras, one of the funders and sponsor of the MVA85A trial. Ann Ginsberg: I am currently the Chief Medical Officer for Aeras. Aeras was one of the funders and sponsor of the MVA85A trial.
Re: Oxford TB vaccine study calls into question selective use of animal data
Title: Vaccine development could advance better within the realm of Biotech Companies than in Academia.
Author: Juraj Ivanyi, Mucosal and Salivary Biology Division. Guy’s Campus of Kings College London. St Thomas’ Street, London SE1 1UL. UK.
Two BMJ Editorials commented on the general implications from the recent ‘Investigation-Feature’ article, which implied vexatious ramifications in the handling of animal testing data and of a clinical trial on the ‘Oxford TB vaccine' 1. I wish to draw attention to a different general aspect, namely on the current proportions, at which medical ‘Research & Development’ (R&D) is allocated between UK academic institutions and the Biotech Industry, which could have led to the reported dilemmas.
From the ‘historical’ angle, during the 1950-1970 decades, academic staff at University Medical Faculties shared responsibilities for research, teaching and patients care, but industrial links, were less common and were of lower esteem. On the other hand, it has been in the domain of pharmaceutical companies to engage in the R&D and clinical trials on potential therapeutics, vaccines and diagnostics. Large companies have suitable infrastructure, represented by separate departments, dedicated to the preclinical R&D and to the setting up and monitoring of clinical trials. Since about the 1980s, this pattern changed dramatically: favouring and prioritising of translational research at Universities, encouraged by the preferences of both governmental and charitable grant funding agencies.
The problems discussed by the BMJ article may represent a by-product of the above quoted institutional shift, which landed the initiative for vaccine ‘Development’ and clinical testing to Academia, rather than Industry. The institutionally managed framework of scientists within companies could deliver perhaps more comprehensively the compulsory registration of information from preclinical to clinical stages of evaluation. Implementation of this demanding and expensive activity might be more effective within the structure of leading biotech companies, which can be focused on targets, rather than in medical academia, which needs to split its efforts, to comply also with its substantial teaching and/or clinical obligations. Some ‘shift back’ to the previous balance of engagement, reflected by strengthening the ‘fundamental’ research platform at Academia while approval of public funding for life-saving health targets by biotech industry could be mutually beneficial.
References:
1. Cohen D. Oxford vaccine study highlights pick and mix approach to preclinical research. BMJ2017;360:j5845. doi:10.1136/bmj.j5845.
Funding: EMI-TB, EC Horizon 2020 Grant (2015-18).
Competing interests: No competing interests