Feasibility, Potential Value and Limitations of Establishing a Closely Monitored Challenge Model of Experimental COVID-19 Infection and Illness in Healthy Young Adult Volunteers FINAL REPORT World Health Organization Advisory Group Tasked to Consider the Feasibility, Potential Value and Limitations of Establishing a Closely Monitored Challenge Model of Experimental COVID-19 Infection and Illness in Healthy Young Adult Volunteers This is a draft. The content of this document is not final, and the text may be subject to revisions before publication. The document may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means without the permission of the World Health Organization. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 2 EXECUTIVE SUMMARY 6 CLINICAL ISSUES 7 SELECTION OF CHALLENGE VIRUS STRAINS AND OF A BSL-3 GMP MANUFACTURER 8 MEASUREMENT OF IMMUNE RESPONSES AND OF VIRUS SHEDDING 8 SUMMARY COMMENT 9 ADVISORY GROUP RECOMMENDATIONS 10 1. PREAMBLE 12 2. WHO’S ACTIVITIES TO ACCELERATE COVID-19 VACCINE DEVELOPMENT AND CLINICAL TESTING 12 2.1. A multi-center, multi-vaccine randomized, placebo-controlled trial ...................................... 12 2.2. Assessing a possible role for experimental challenge studies .............................................. 13 3. WHY NOW FOR AN ADVISORY GROUP TO CONSIDER THE FEASIBILITY, POTENTIAL VALUE AND LIMITATIONS OF ESTABLISHING A CLOSELY MONITORED CHALLENGE MODEL OF EXPERIMENTAL COVID-19 INFECTION AND ILLNESS IN HEALTHY YOUNG ADULT VOLUNTEERS? 20 3.1. Terms of Reference ...................................................................................................................... 20 3.2. Logistics, timelines and costs .................................................................................................... 21 3.3. Some uses of a model, if established ........................................................................................ 22 3.4. Other related issues ..................................................................................................................... 22 3.5. Deliverables .................................................................................................................................. 22 4. INTRODUCTION TO THE TASK 23 4.1. Formation of Subgroups and Teams ......................................................................................... 25 4.2. A Cautious Two-Stage Approach ............................................................................................... 26 5. CLINICAL ISSUES 29 5.1. A Clinical Protocol Synopsis Prepared by the Subgroup on Clinical Trial Issues ............... 29 6. ELEMENTS OF A CLINICAL PROTOCOL 29 6.1. Volunteer selection ...................................................................................................................... 29 3 6.2. Size of initial groups .................................................................................................................... 31 6.3. Endpoints to be achieved with SARS-CoV-2 challenge model. .............................................. 32 6.4. Method of administration ............................................................................................................ 34 6.5. Safety Monitoring during inpatient stay .................................................................................... 34 6.6. Discharge criteria ......................................................................................................................... 34 6.7. Follow-up ...................................................................................................................................... 35 6.8. Laboratory studies ....................................................................................................................... 35 6.9. Treatment protocols .................................................................................................................... 36 7. ISOLATION UNITS FOR USE IN A SARS-COV-2 CHALLENGE 36 7.1. Capabilities available on the unit ............................................................................................... 38 7.2. Medical expertise/support care available on the unit .............................................................. 38 7.3. Precautions for staff/third parties .............................................................................................. 39 7.4. Measures to address volunteers who wish to leave the study before completion ............... 39 7.5. Handling of the SARS-CoV-2 challenge virus ........................................................................... 40 7.6. Efficacy studies ............................................................................................................................ 40 8. CONSENT FORM 41 9. VOLUNTEER COMPREHENSION TEST 41 10. SELECTION OF VIRUSES TO BE USED IN CHALLENGE STUDIES 43 10.1. Points to consider in selecting a SARS-CoV-2 challenge virus strain ................................. 43 11. MANUFACTURE OF GMP BATCHES OF SARS-COV VIRUS STRAINS FOR VOLUNTEER CHALLENGE STUDIES 46 11.1. ...................................................................................................................................................... 46 11.2. Criteria for selection of a manufacturer of the challenge agents ...................................... 48 11.3. Some Advisory Group suggestions to be discussed with the manufacturer ..................... 49 12.REPORT OF THE SUBGROUP ON MEASUREMENT OF IMMUNE RESPONSES PRE- AND POST-CHALLENGE 50 12.1. Background ................................................................................................................................ 50 12.2. Principles of immunologic study of volunteer challenges with SARS-CoV-2 .................. 50 4 12.3. The volunteer challenge model can contribute to identification of ...................................... 51 13. SUBGROUP ON DETECTION OF SARS-COV-2 IN CLINICAL SPECIMENS POST-CHALLENGE 54 13.1. Nucleic acid assay ..................................................................................................................... 54 APPENDIX B ........................................................................................................................................ 59 APPENDIX C ........................................................................................................................................ 63 5 Executive Summary Recognizing the helpful role that experimental challenge studies in healthy adult volunteers have played in the development of certain vaccines, some have advocated a role for such studies with virulent SARS-CoV-2. However, several factors collectively warrant that special caution must be taken in working with SARS-Cov-2, including: o the severity of COVID-19 disease, as evidenced by its high case fatality risk in certain sub- populations (elderly, diabetics, hosts with pre-existing pulmonary and cardiac disease); o severe disease requiring ventilator support and deaths (albeit uncommon) also occurs in young adults, although risk factors for these outcomes in this age group remain uncharacterized; increasing recognition of severe thromboembolic events in young adults; o the high transmissibility of SARS-CoV-2 from person-to-person directly by respiratory droplets and at further distances by airborne droplet nuclei; o the virus’ ability to remain viable on some fomites for hours; with each passing month, new acute presentations and forms of illness that SARS-CoV-2 infection can elicit have been described; o finally, as of early June 2020, a reliable “rescue treatment” has not yet been identified that can predictably arrest the progression of COVID-19 illness from a mild/moderate illness to serious, potentially life-threatening, illness. Understandably, among experienced challenge model investigators the topic of undertaking challenge studies with fully virulent SARS-CoV-2 has generated discussion about whether the conditions can be assured to perform challenge studies safely and what the priority goals should be for such studies. Taking into account the reasons for caution cited above, if conditions were deemed suitable to undertake development of a closely monitored SARS-CoV-2 challenge model in healthy young adult volunteers, important information could accrue such as: o to determine whether an initial challenge infection confers significant protection against a subsequent challenge with the homologous virus (and perhaps in subsequent studies to address whether infection-derived protection extends to other virus clades); o to identify immunologic correlates of protection against clinical illness and shedding of virus that might accompany recovery from a prior experimental challenge with SARS-CoV-2; o to allow studies of different COVID-19 vaccine candidates to estimate the extent to which they protect and whether protection, if observed, is against COVID-19 clinical disease or against SARS-CoV-2 infection, or both; and o to contribute to the development of correlates of protection against clinical illness and against shedding of virus in vaccinated volunteers; to compare the protection afforded by