Prevention and Prophylaxis of SARS-CoV-2 Infection
Last Updated: August 27, 2020
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies; III = Expert opinion
General Prevention Measures
Most transmissions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are thought to occur through respiratory droplets, and the risk of transmission can be reduced by covering coughs and sneezes and maintaining a distance of at least 6 feet from others. When consistent distancing is not possible, face coverings may further reduce the spread of droplets from individuals with SARS-CoV-2 infection to others. Frequent handwashing is also effective in reducing the risk of infection.1 Health care providers should follow the Centers for Disease Control and Prevention (CDC) recommendations for infection control and appropriate use of personal protective equipment.2
Vaccines for SARS-CoV-2 are aggressively being pursued. Vaccine development is typically a lengthy process, often requiring multiple candidates before one proves to be safe and effective. To address the current pandemic, several platforms are being used to develop candidate vaccines for Phase 1/2 trials; those that show promise are rapidly moving into Phase 3 trials. Several standard platforms, such as inactivated vaccines, live-attenuated vaccines, and protein subunit vaccines, are being pursued. Some novel approaches are being investigated, including DNA-based and RNA-based strategies and replicating and nonreplicating vector strategies, with the hope of identifying a safe and effective SARS-CoV-2 vaccine that can be used in the near future.3,4
- The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of any agents for SARS-CoV-2 pre-exposure prophylaxis (PrEP), except in a clinical trial (AIII).
At present, there is no known agent that can be administered before exposure to SARS-CoV-2 (i.e., as PrEP) to prevent infection. Clinical trials are investigating several agents, including emtricitabine plus tenofovir alafenamide or tenofovir disoproxil fumarate, hydroxychloroquine, and supplements such as zinc, vitamin C, and vitamin D. Studies of monoclonal antibodies that target SARS-CoV-2 are in development. Please check ClinicalTrials.gov for the latest information.
- The Panel recommends against the use of any agents for SARS-CoV-2 post-exposure prophylaxis (PEP), except in a clinical trial (AIII).
At present, there is no known agent that can be administered after exposure to SARS-CoV-2 infection (i.e., as PEP) to prevent infection. Potential options for PEP that are currently under investigation include chloroquine, hydroxychloroquine, lopinavir/ritonavir, nitazoxanide, vitamin super B-complex, and vitamin D. Other post-exposure preventive strategies that are in development include the use of SARS-CoV-2 monoclonal antibodies and convalescent plasma. Please check ClinicalTrials.gov for the latest information.
Clinical Trial Data
Both chloroquine and hydroxychloroquine have in vitro activity against SARS-CoV and SARS-CoV-2.5,6 A small cohort study without a control group has suggested that hydroxychloroquine might reduce the risk of SARS-CoV-2 transmission to close contacts.7
Randomized, Double-Blind, Controlled Trial of High-Risk or Moderate-Risk Occupational or Household Exposures
A randomized, double-blind, controlled trial included 821 participants who self-enrolled in the study using an internet-based survey. Study participants had either high or moderate risk of occupational exposures (66% of participants) or household exposures (34% of participants). High-risk exposure was defined as being within 6 feet of an individual with confirmed SARS-CoV-2 infection for more than 10 minutes while not wearing a face mask or eye shield (87.6% of participants), and moderate-risk exposure was defined as the same distance and duration of exposure while wearing a face mask but no eye shield (12.4% of participants).8
Participants were randomized to receive placebo or hydroxychloroquine sulfate given once at a relatively high dose of 800 mg, followed by 600 mg 6 to 8 hours later, then 600 mg once daily for 4 additional days. Because enrollment was done online, study drugs were sent by overnight mail, resulting in more than 50% of participants initiating their first dose 3 to 4 days after exposure to SARS-CoV-2.8
A total of 107 participants developed the primary outcome of symptomatic illness, confirmed either by a SARS-CoV-2 positive molecular test or, if testing was not available, by a compatible, COVID-19-related syndrome based on CDC criteria. Due to limited access to molecular diagnostic testing, SARS-CoV-2 infection was confirmed in only 16 of the 107 participants (15%). There was no statistically significant difference in the incidence of the primary outcome (symptomatic illness) between the hydroxychloroquine group and the placebo group (11.8% vs. 14.3%, respectively; P = 0.35). There were more adverse events in the hydroxychloroquine group; mostly nausea, loose stools, and abdominal discomfort; with no serious adverse reactions or cardiac arrhythmias.8
This study had several important limitations, including:
- Initiation of therapy was delayed for at least 3 days after exposure to SARS-CoV-2 in most participants.
- Only 15% of participants who reached the primary outcome had SARS-CoV-2 infection confirmed by molecular diagnostics.
- The study population was young (with a median age of 40 years) and consisted of participants who had a relatively low risk of severe COVID-19.
It is notable that although high doses of hydroxychloroquine were associated with an increase in the frequency of adverse events, the reported adverse events were mostly mild, with no serious events reported.
Cluster-Randomized Trial of High-Risk Exposures in SpainThis study has not been peer reviewed.
An open-label, cluster-randomized trial included 2,314 asymptomatic contacts of 672 COVID-19 cases in Spain. Study participants were health care or nursing home workers (60.3%), household contacts (27.7%), or nursing home residents (12.7%) who were aged ≥18 years and documented to have spent >15 minutes within 2 meters of a polymerase chain reaction (PCR)-positive COVID-19 case during the 7 days prior to enrollment.9
Participants who were epidemiologically linked to a PCR-positive COVID-19 case were defined as study clusters (called rings). All contacts in a ring were simultaneously cluster-randomized 1:1 to either usual care (the control arm) or hydroxychloroquine 800 mg once daily for 1 day followed by 400 mg once daily for 6 days (the intervention arm). Participants were informed of their allocated study arm after being randomized to the intervention or control arm and signing a consent form. The primary outcome was onset of laboratory-confirmed COVID-19, defined as illness with at least one of the following symptoms: fever, cough, difficulty breathing, myalgia, headache, sore throat, new olfactory and taste disorders, or diarrhea; AND a positive SARS-CoV-2 PCR test. A secondary outcome was onset of SARS-CoV-2 infection defined as either a SARS-CoV-2 PCR positive test OR the presence of any of the symptoms compatible with COVID-19. Additional secondary outcomes were development of serological positivity at Day 14 and safety up to 28 days from treatment initiation.
The baseline characteristics of the participants were similar between the two study arms, including coexisting disease, number of days of exposure before enrollment and randomization, and type of contact. A total of 138 (6%) study participants developed PCR-confirmed, symptomatic SARS-CoV-2 infection, with no statistical difference for this outcome between the control and intervention arms (6.2% vs. 5.7%, respectively; risk ratio 0.89; 95% CI, 0.54–1.46). There was also no statistical difference between the study arms in the incidence of either PCR-confirmed or symptomatically compatible COVID-19, which occurred in 18.2% of participants, 17.8% in the control arm and 18.7% in the intervention arm (risk ratio 1.04; 95% CI, 0.77–1.41). Similarly, there was no statistical difference between the arms in the rate of positivity for SARS-CoV-2 immunoglobulin (Ig) A and/or IgG (8.7% in the control arm and 14.3% in the intervention arm; risk ratio 1.6; 95% CI, 0.96–2.69). There were more adverse events among the hydroxychloroquine-treated participants (51.6%) than among the controls (5.9%), although most of the adverse events were mild, including gastrointestinal events, nervous system disorders, myalgia, fatigue, or malaise. No serious adverse events were attributed to the study drug.
This study had several limitations, including:
- It lacked a placebo comparator, which could have had an impact on safety reporting.
- Data regarding the extent of the exposure to the index cases was limited.
- For >50% of the study participants, the time from exposure to the index case to randomization was ≥4 days.
- Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): how to protect yourself & others. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed August 25, 2020.
- Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): infection control guidance for healthcare professionals about coronavirus (COVID-19). 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control.html. Accessed August 25, 2020.
- Lurie N, Saville M, Hatchett R, Halton J. Developing COVID-19 vaccines at pandemic speed. N Engl J Med. 2020;382(21):1969-1973. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32227757.
- World Health Organization. Draft landscape of COVID-19 candidate vaccines. 2020. Available at: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines. Accessed August 25, 2020.
- Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020;71(15):732-739. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32150618.
- Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318.
- Lee SH, Son H, Peck KR. Can post-exposure prophylaxis for COVID-19 be considered as an outbreak response strategy in long-term care hospitals? Int J Antimicrob Agents. 2020;55(6):105988. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32305587.
- Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N Engl J Med. 2020;383(6):517-525. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492293.
- Mitja O, Ubals M, Corbacho M, et al. A cluster-randomized trial of hydroxychloroquine as prevention of COVID-19 transmission and disease. medRxiv. 2020:Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.07.20.20157651v1.