Re: Learning lessons from MVA85A, a failed booster vaccine for BCG
13 August 2019
Since the correspondence (1), questioning the evidence for efficacy of the influenza vaccine MVA-NP+M1 claimed by Lillie et al, there have been some developments that should be recorded. I am grateful to Thomas Evans MD, CEO Vaccitech, for discussion and fact checking this letter.
1) The claim for efficacy in humans of the MVA-NP+M1 in the Lillie study that I challenged (1) has now been formally corrected in the form of an “erratum” published in the Journal Clinical Infectious Diseases, acknowledging that the p value quoted in the article was not correct (https://academic.oup.com/cid/article/69/1/195/5497806). The path to obtaining publication of this “erratum” was prolonged and tiresome: my observations were published in the BMJ on 23 January 2018, and it was not until 23 May 2019 that the “erratum” appeared in C.I.D. After a prolonged correspondence, and provision of independent reviews by a senior statistician invited by the Oxford Vaccine Oversight Committee, and the C.I.D statistics editor, a form of words was eventually found.
2) Despite being dismissive in their response to my request for performing a properly powered double blind challenge study with MVA-NP+M1 (1), Vaccitech have now been funded by BARDA $8.5 million for such a study conducted by SGS Life Sciences in Belgium (clinicalTrials.gov Identifier: NCT03883113). The objective pre-defined primary end point is viral shedding. BARDA's statistician and modelers will review the statistical plan before and after data analysis and unblinding. This should establish once and for all whether MVA-NP+M1 has any efficacy in humans as a “booster vaccine” for influenza.
3) The poorly designed “INVICTUS” study (ClinicalTrials.gov Identifier: NCT03300362), that I criticised (1) and referred to the Oxford Vaccine Oversight Committee because it combined standard subunit vaccination with MVA-NP+M1, but lacked any virological end-point, or specificity controls, has been “terminated” with the reason given as “change to recommended seasonal flu vaccine in UK”. This refers to the recommendation to upgrade from quadrivalent to MF59 adjuvanted trivalent subunit vaccine in those aged 65 and over (https://www.nhs.uk/conditions/vaccinations/flu-influenza-vaccine/).
4) Without waiting for the results of the challenge study NCT03883113 to establish whether MVA-NP+M1 has any efficacy, the INVICTUS study has been replaced by a similar but much larger phase 2b field study, involving 6,000 participants (NCT03880474) to be conducted in Australia, but this time at least with an objective primary end-point of “incidence rate of laboratory confirmed influenza using reverse transcription polymerase chain reaction (RT-PCR) on deep nasal swab samples to record confirmed cases of influenza.” This has improved the design, and steps have also been taken to administer the MVA-NP+M1 and the subunit vaccine in different deltoids with the aim of minimising the nonspecific adjuvant effect of MVA.
My view (1) is that this field trial should have been postponed until the evidence for efficacy of MVA-NP+M1 from the statistically sound challenge study NCT03883113 was available, before exposing another 1100 participants to this recombinant Pox Virus this year. At least the Patient Information Leaflet should have explained to volunteers that to date this vaccine has not shown any efficacy in humans, and minimal evidence in animals (1), that a similar design of vaccine failed to prevent TB (1, 2), and that if they wished they could postpone their decision to participate until the following influenza season, when the results of the efficacy study NCT03883113 should be available. I have repeatedly requested to see the Patient Information Leaflet for the field trial NCT03880474, but have been declined access by Thomas Evans MD, CEO at Vaccitech, on the basis that it is “proprietary” to the company.
(1) Rapid Responses to Editorial Learning lessons from MVA85A, a failed booster vaccine for BCG (https://www.bmj.com/content/360/bmj.k66/rapid-responses).
(2) Cochrane Database Syst Rev. 2019. MVA85A vaccine to enhance BCG for preventing tuberculosis. Kashangura R, Jullien S, Garner P, Johnson S.(https://www.ncbi.nlm.nih.gov/pubmed/31038197#)
Competing interests: I lead a group developing a single cycle influenza virus "S-FLU" as a broadly protective vaccine.