The BMJ has published an investigation into how researchers interpreted results of animal studies – before moving to human clinical trials – to test a new tuberculosis vaccine.
Prof. Andrew Pollard, Professor of Paediatric Infection and Immunity, University of Oxford said:
“This investigation ignores an important aspect of vaccine development, which is not well understood by those who don’t work in vaccine development. Before any vaccine is given to humans, national regulators in Europe and the United States require investigators to provide data showing that the vaccine is safe and that it might potentially work using appropriate animal models. However, it is well recognised by vaccine developers and experts on the immune system that immune responses in animals don’t necessarily predict whether a vaccine will work when tested in people. Animals are not humans. This means that there are many examples of vaccines that appeared to work well in animals but failed in human trials. It is also likely that there will be some products which were dropped as a result of poor results in animals that might had protected humans.”
Prof. Anne Cooke, Vice-President of the British Society for Immunology, said:
“Vaccines, which work by boosting a specific immune response against an infectious agent, are one of the most effective public health interventions and have saved millions of lives. The development of a safe and effective vaccine takes many years and needs to go through many different stages of testing, including work on cells, testing on animals and finally clinical trials on humans.
“At each stage of development, it is important that experiments are meticulously and rigorously designed and analysed to allow us to be confident in their findings and allow proper evaluation of the safety and efficacy of the drug by academics and ethical committees. This is particularly true for pre-clinical experiments (i.e. those involving animals) and clinical trials conducted on humans. While the scientific community aims to reduce the number of animals used in research, this is currently a crucial step in testing a new drug before it is given to humans in clinical trials. Experiments carried out on animals should always have a clear aim and adhere to the principles of the 3Rs (replacement, reduction, refinement) to minimise animal numbers and suffering. Studies should only progress to clinical trials in humans if there is clear evidence from animal models showing safety and efficacy of the drug concerned.
“The development of new vaccines has potential to deliver huge public health benefits to tackle diseases that affect millions of people worldwide. To realise this potential, as researchers working in this field, we have a responsibility to ensure that the experiments we carry out are rigorous and that we are transparent and open with the scientific community and the public about their results.”
Dr Marcus Dorner, Non-Clinical Senior Lecturer in Immunology, Imperial College London, said:
“Even though the outcome of this study, which was conducted according to the standard of practice, is disappointing, it is important to keep in mind that vaccine trials especially are very challenging. Even though numerous species were tested, the natural hosts for Tuberculosis are humans. Even though model systems exist, they do not always accurately recapitulate every aspect of TB infection in humans.
“It is often difficult to compare results from preclinical studies involving not only vaccine, but also novel drug candidates to those ultimately observed in humans. This is largely due to genetic and immunological differences between the animal species used in those studies and humans. The required evaluation in several species aims at “normalising” these differences and to prevent missing adverse effects. Nevertheless, one must appreciate that mice are not humans and clinical trials are unfortunately often the only definitive proof for efficacy or safety. However, studies in animal models have their deserved place in the drug and vaccine development process in that they allow the exclusion of clearly ineffective or unsafe candidates. Several recent studies have revealed that novel approaches and “out-of-the-box” thinking are needed to improve the selection and shortlisting process prior to engaging in clinical trials in humans. This was also appreciated by the US Food and Drug Administration (FDA), who recently recommended the use of “humanised mice” for drug safety and efficacy. This is based on reconstituting a human immune system or a human liver in an immunodeficient mouse, thus enabling the evaluation of safety and efficacy in a platform containing actual human cells. This, combined with more stringent experimental design and regulatory guidance could help improve the decision-making process for novel clinical trials.”
Prof. Mike Turner, Head of Infection and Immunobiology, Wellcome, said:
“The MVA85 clinical trials were all conducted to the highest standard and complied with all requirements of the relevant regulatory bodies and ethical oversight committees in three countries. The decision to test this candidate vaccine was correct and based on robust, positive data from smaller trials in humans that showed that the candidate vaccine was safe and that it might be effective.
“The efficacy trial demonstrated no safety concerns but found that the vaccine candidate was not effective in preventing TB infection. Lessons from this trial have informed the development of the next-generation vaccines, as well as TB diagnosis in infants.
“Human trials do not always generate the same results as animal testing, which is why results in animal models are typically only one of a set of considerations in determining whether to move research forward. After the safety of the vaccine had been tested, animal studies continued in order to provide further understanding into the mechanics of how the vaccine works. This knowledge can help researchers make a better vaccine in the future.”
Dr Vicky Robinson, Chief Executive, National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), said:
“This makes uncomfortable reading even though many of the issues raised are not new. The need for transparency in animal research has never been greater, not least for ensuring public confidence. The focus of everyone involved in animal research must be on high quality studies that are properly designed and reported. Integral to this is a much greater emphasis on challenging upfront whether the experiments are absolutely necessary and on ensuring that the information obtained can actually be used, and indeed reliably used, by others including academics, regulators and the pharmaceutical industry.”
* ‘Oxford vaccine study highlights pick and mix approach to preclinical research’ by Cohen published in The BMJ on Wednesday 10 January.
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Prof. Andrew Pollard: Prof Pollard is also employed by the University of Oxford but works in a different department to Prof McShane. He did not work with her on the development of this vaccine.
Prof. Anne Cook: No conflicts of interest
Dr Marcus Dorner: No conflicts of interest.
Prof. Mike Turner: Helen McShane has a Wellcome Investigator award and the MVA85A vaccine research was part funded through Wellcome. She also chairs Wellcome’s Clinical Interview committee and is a member of Wellcome’s Science strategic advisory committee.
Dr Vicky Robinson: “MRC and Wellcome are referred to in the editorial – both fund the NC3Rs, with the MRC being the major funder of the NC3Rs. None of the work featured in the editorial is funded by the NC3Rs. Professor Helen McShane from the University of Oxford is funded by the NC3Rs to develop an in vitro mycobacterial challenge model. See https://www.nc3rs.org.uk/developing-and-validating-vitro-mycobacterial-challenge-model-facilitate-tb-vaccine-research-and. Dr Emily Sena from the University of Edinburgh who is a co-author of the systematic review paper on MVA85A had a grant from the NC3Rs from 2012 to 2015 (see https://www.nc3rs.org.uk/reduction-refinement-animal-models-neuropathic-pain-using-systematic-review-meta-analysis) and is a co-investigator on an NC3Rs award to Professor Malcolm MacLeod from the University of Edinburgh to develop an online resource to assist scientists with conducting systematic reviews and meta-analyses of animal research (see https://www.nc3rs.org.uk/syrf%E2%80%93-camarades%E2%80%93nc3rs-vivo-systematic-review-and-meta-analysis-facility). Dr Sally Sharpe from Public Health England, the lead author on the non-human primate study referred to in the editorial, is a co-investigator on an NC3Rs grant to adopt an in vitro model for assessing TB vaccine candidates (see https://www.nc3rs.org.uk/transfer-non-human-primate-nhp-vitro-functional-assay-early-evaluation-tb-vaccine-candidates-and). The NC3Rs is leading a programme of work to improve the design, analysis and reporting of animal research. This includes the online Experimental Design Assistant (see https://www.nc3rs.org.uk/experimental-design-assistant-eda) and the ARRIVE reporting guidelines (see https://www.nc3rs.org.uk/arrive-guidelines).”