key: cord-0963922-51rc48i4
authors: Smit, Mikaela; Marinosci, Annalisa; Agoritsas, Thomas; Ford, Nathan; Calmy, Alexandra
title: Prophylaxis for COVID-19: a systematic review
date: 2021-01-18
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.01.013
sha: 089e158480ed8ce0a64df13dd24ed8f5589630f2
doc_id: 963922
cord_uid: 51rc48i4

BACKGROUND: While the landscape of vaccine and treatment candidates against the novel coronavirus (COVID-19) has been reviewed systematically, prophylactic candidates remain unexplored. OBJECTIVES: Map pre- and post-exposure prophylactic (PrEP and PEP) candidate for COVID-19. DATA SOURCES: PubMed/Medline, Embase, International Committee of Medical Journal Editors and International Clinical Trials Registry Platform clinical trial registries and MedRxiv. STUDY ELIGIBILITY CRITERIA AND PARTICIPANTS: All studies in humans or animals and randomized clinical trials (RCTs) in humans reporting primary data on prophylactic candidates against COVID-19, excluding studies focused on key populations. INTERVENTIONS: PrEP and PEP candidate for COVID-19. METHODS: Systematic review (SR) and qualitative synthesis of COVID-19 PrEP and PEP studies and RCTs complemented by search of MedRxiv and PubMed and Embase for studies reporting RCTs outcomes since SR search completion. RESULTS: We identified 13 studies (out of 2,119 database records) and 117 RCTs (out of 5565 RCTs in the registries) meeting inclusion criteria. Non-RCT studies reported on cross-sectional studies using hydroxychloroquine (HCQ) in humans (n=2) or reported on animal studies (n=7) most of which used antibodies. All five completed RCTs focused on the use of HCQ as either PrEP or PEP and these and the cross-sectional studies reported no prophylactic effect. The majority of ongoing RCTs evaluated HCQ or other existing candidates including non-SARS-CoV-2 vaccines, anti(retro)virals, or use of vitamins and supplements. CONCLUSIONS: The key message from completed studies and RCTs seems to be that HCQ does not work, there is little evidence regarding other compounds with all RCTs using candidates other than HCQ still ongoing. It remains to be seen if the portfolio of existing molecules being evaluated in RCTs will identify successful prophylaxis against COVID-19 or if there is a need for the development of new candidates.

The world is facing the biggest global public health emergency of this generation as a result of 2 the novel coronavirus pandemic. The severe acute respiratory syndrome coronavirus type 2 3 (SARS-CoV-2) is the causative agent for coronavirus disease 19 (COVID-19), characterised by 4 rapid human-to-human transmission and important pathogenicity [1] . At the time of writing this 5 article, the world has passed a new worrying milestone of one million confirmed COVID-19 6 deaths [2] . 7 8 Beyond the human suffering, the COVID-19 pandemic has caused unprecedented pressures on 9 healthcare systems and supply chains [3, 4] , with the ensuing lock-downs resulting in growing 10 frailties for national economies [5, 6] . Containing the COVID-19 pandemic will necessitate a 11 multi-pronged strategies including effective vaccination, prophylaxis and treatment, in addition 12 to existing protective measures such as social distancing, masking and hand hygiene [7] [8] [9] . This 13 pandemic has resulted in an unparalleled galvanization of the medical and scientific community 14 to identify pharmacological candidates for its prevention and treatment. While the landscape of 15 vaccine [10,11] and treatment [12, 13] candidates has been reviewed systematically, evidence 16 synthesis of prophylactic candidates remains unexplored. 17

In this review we aim to address this gap by performing a systematic review of all published 19 studies and clinical trials registries for prophylactic candidates to map out the landscape of 20 existing and future candidates. As this is a fast-moving field, we aim to provide an updated status 21 of the evidence by performing an updated systematic review in the near future. 22

We carried out a systematic review according to PRISMA guidelines [14] , to identify studies 26 reporting on prophylactic candidate for COVID-19 and/or SARS-CoV-2. Prophylactic 27 candidates were defined as any drug, biologics-based molecule, dietary supplements or herbal 28 remedies used to prevent infection of disease, regardless of its administration route. This 29 included both pre-and post-exposure prophylaxis (PrEP and PEP) but excluded SARS-CoV-2 30 vaccines and therapeutic interventions for individuals who are already infected. We excluded 31 J o u r n a l P r e -p r o o f 4 studies focused on populations with specific co-morbidities, including those undergoing specific 32 surgical procedures or with specific co-morbidities (Table 1) . 33 34 PubMed/Medline, and Embase, were searched from inception to and including 13 th December 35 2020; searches were not restricted by language or quality of study and a broad search strategy 36 was used combining the terms; 'SARS-CoV-2' OR 'COVID-19', AND 'prophylaxis' OR 37 'prophylactic'. 38 39 and International Clinical Trials Registry Platform (ICTRP)) (Supplement Table S1 ) for any 45 randomized clinical trials (RCTs) of prophylaxis against COVID-19 and/or SARS-CoV-2, 46 focusing on RCTs evaluating the impact of prophylactic candidates on SARS-CoV-2 or COVID-47

The ICMJE and ICTRP search was conducted up to 13 th December 2020 using the same terms as 50 the database search and limiting to interventional studies where possible. Furthermore, MedRxiv 51 was searched from inception to 30 th December 2020 for any studies reporting the outcomes of 52

prophylaxis RCTs, using the search terms "COVID-19" AND "prophylaxis" AND "Trial". 53 independently according to pre-specified inclusion and exclusion criteria ( Table 1) . Where two 61 studies reported on the same study, the most recent one reporting on the impact of the 62 prophylaxis was chosen. Where the same RCT was found in two or more registries or an RCT 63 was also found in a published article, it was only reported once. Conflicts were resolved by the 64 two reviewers on a case-by-case basis, with conflicts resolved with a third reviewer (AC) where 65 needed. Reference lists of included full-text articles were screened to identify additional studies. 66

The screening and selection process are presented in Figure 1 . 67

Data extraction and synthesis 70

All data was extracted in Microsoft Excel by MS and AM, in a data extraction form which was 71 piloted on five studies and five clinical trials. All data extraction was quality checked by the 72 other co-author for quality assurance. Data extracted from full-text articles included first author, 73

publication year, country of study, study type, prophylaxis type, molecule name or combination 74 and class, host, study outcome. For RCTs data extraction included trial title, country of sponsor, 75

prophylaxis type, name of molecule or combination and class, target population, sample size and 76 status. (Table 3) . 23 24 J o u r n a l P r e -p r o o f 

The world is certainly not unaccustomed to infectious diseases. From the discovery of penicillin 33 at the start of the 20 th century [45] and the fight against human immunodeficiency virus (HIV) 34 which started in the 1980s [46, 47] , the scientific and medical community has demonstrated its 35 ability to galvanise rapidly in order to collate knowledge on transmission, prevention and 36 treatment of infectious diseases. COVID-19 has undisputedly brought the urgency to understand 37 an infectious disease to a new level. However, it has also highlighted the importance of 38 coordinated and aligned efforts, in order to identify effective strategies to fight the pandemic. 39

The large number of prophylactic trials testing the same prophylactic candidate, for example, 40 highlights two points. While the world stood still to halt the spread of the disease, the medical 41 and scientific community has worked under never-before seen pressure, resulting in often 42 fragmented efforts. It has made it hard for communities to coordinate their efforts and join 43

forces. Yet, every trial faces limitations, from selection bias, to sample size issues. Pooling the 44 wealth of clinical trial data that is being produced will allow to construct a clearer of the true 45 effect of these candidates. 

The transmission and diagnosis of 2019 novel coronavirus infection disease (COVID-92 19): A Chinese perspective

Coronavirus death toll reaches 1 million -how did we get here? New

Pressure on Healthcare Systems: Coping with Demand for ICU and Hospital Beds | European Data 97

Covid-19: how doctors and healthcare 100 systems are tackling coronavirus worldwide

The Global Economic Outlook During the COVID-19 Pandemic: A Changed World

The impact of the coronavirus (COVID-19) crisis on development finance

Estimating the effects of 108 non-pharmaceutical interventions on COVID-19 in Europe

The impact of COVID-111 19 and strategies for mitigation and suppression in low-and middle-income countries

Vaccine Efficacy [11

COVID-19): A Systematic Review of Clinical Trials

Drug treatments for covid-123 19: living systematic review and network meta-analysis

A systematic review of trial 126 registry entries for randomized clinical trials investigating COVID-19 medical prevention and 127 treatment

Preferred reporting items for systematic reviews and 129 meta-analyses: the PRISMA statement

Assessing risk of bias in a non-randomized study n.d. 135 /handbook/current/chapter

RoB 2: A revised Cochrane risk-of-bias tool for randomized trials n

/bias/resources/rob-2-revised-cochrane-risk-bias-tool-randomized-trials (accessed October

Hydroxychloroquine for prophylaxis and 140 treatment of COVID-19 in health-care workers

Hydroxychloroquine pre-143 exposure prophylaxis for COVID-19 in healthcare workers

LY-CoV555, a 146 rapidly isolated potent neutralizing antibody, provides protection in a non-human primate model 147 of SARS-CoV-2 infection

Rapid identification of a human 149 antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 150 infection

Isolation of potent SARS-CoV-2 152 neutralizing antibodies and protection from disease in a small animal model

Ultrapotent human 155 antibodies protect against SARS-CoV-2 challenge via multiple mechanisms

Favipiravir at 158 high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas 159 hydroxychloroquine lacks activity

Hydroxychloroquine Workers: A Randomized Clinical Trial

Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome 170

Coronavirus 2 Infection : A Randomized Trial

Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a 177 randomized trial

Hydroxychloroquine use 179 against SARS-CoV-2 infection in non-human primates

Hydroxychloroquine as Prevention of Covid-19 Transmission and Disease

Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis among Health Care 186 Workers: A Randomized Clinical Trial

COVID-19 randomised trial protocols: rapid 189 publication without barriers

Comparison of randomized controlled trials discontinued or 191 revised for poor recruitment and completed trials with the same research question: a matched 192 qualitative study

Within a large healthcare system, the incidence of positive COVID-19 194 results and mortality are lower in patients on chronic hydroxychloroquine therapy n

Prophylaxis of COVID-19 Transmission-A Preliminary Report of a Retrospective Cohort Study

Analysis of the prophylactic effect of thymosin drugs on COVID-200 19 for 435 medical staff: A hospital-based retrospective study

Echinacea purpurea preparation, against coronaviruses, including common cold 207 coronavirus 229E and SARS-CoV-2

The effect of Echinacea spp. 210 on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A 211 rapid review

Development of CRISPR as an Antiviral 215 Strategy to Combat SARS-CoV-2 and Influenza

The Molecular Biology of HIV

Discoverer of penicillin

Kaposi's sarcoma and Pneumocystis pneumonia among 221 homosexual men--New York City and California

Isolation of a T-223 lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS)

*Database search records excluded with reasons: 32 studies did not explore prophylactic candidates or measure outcome; 11 clinical trial protocol; 9 narrative reviews, opinion pieces or case reports; 1 focused on key populations; 1 could not find full-text **RCT

The authors have declared that no competing interests exist. 76 77Authors' contributions 78 MS, AM and AC conceived the paper, formulated the overall aim, scope and lens of the 79 manuscript. MS wrote the protocol and performed the search, and risk of bias. MS and AM 80 carried out the systematic review, extracted the data and wrote the first draft of the manuscript. 81All authors contributed to the re-drafting and finalisation of the manuscript. 82 83 84Financial Disclosure 85The author(s) received no specific funding for this work. 86 87Additional files 88Additional file 1: Supplement 1 89 90