Coronavirus

Common Investigation Protocol for Investigating Suspected SARS-CoV-2 Reinfection

Protocol summary: This protocol is designed to support a common public health investigation into suspected SARS-CoV-2 reinfection cases across jurisdictions. Confirming SARS-CoV-2 reinfection requires advanced laboratory diagnostic support built upon advanced planning to implement this protocol, or a locally adapted version, with referral of specimens to supporting laboratory networks. Data collected with this protocol will…

Protocol summary: This protocol is designed to support a common public health investigation into suspected SARS-CoV-2 reinfection cases across jurisdictions. Confirming SARS-CoV-2 reinfection requires advanced laboratory diagnostic support built upon advanced planning to implement this protocol, or a locally adapted version, with referral of specimens to supporting laboratory networks. Data collected with this protocol will identify potential cases of reinfection, advance understanding of SARS-CoV-2 epidemiology, and inform public health response.

Introduction

Current state of knowledge: A gold-standard confirmation of SARS-CoV-2 reinfection will require confirmation of initial infection and virus detection across two distinct time periods with genetic sequencing data needed to support a conclusion of high probability that reinfection has occurred. Possible SARS-CoV-2 reinfection could be differentiated from persistent viral carriage through a variety of laboratory-based parameters, patient symptomology, and/or epidemiologic links1. However, reinfection cannot be confirmed if clinical specimens from the initial coronavirus disease 2019 (COVID-19) illness are not available.

Reinfection is known to occur with other human coronaviruses (HCoVs) 2. A study in Kenya found that 4%–21% of people infected with endemic coronaviruses (HCoV-229E, NCoV-NL63, and HCoV-OC43) had two or more episodes of infection with the same virus species during a six-month period3. Another study of HCoVs that used an antibody increase as a proxy for reinfection found that reinfections occurred at a median of 30 months but could occur as early as 6 months following the first infection4. However, immunologic data on durability of immunity for SARS-CoV-2 are limited6. Of note, South Korea has documented RT-PCR-confirmed COVID-19 cases that became undetectable by RT-PCR, then subsequently tested positive again by RT-PCR within 35 days due to detection of presumable incomplete (defective) viral genomes, suggesting that reinfection was not detected during that time frame5.

CDC is aware of recent scientific and media reports of cases of suspected SARS-CoV-2 reinfection among persons who were previously diagnosed with COVID-197–9. However, these reports use different testing methods to ascertain reinfection. Because of the need for a common understanding of what constitutes reinfection, CDC proposes this common investigation protocol for identifying cases with a high index of suspicion for reinfection and suggests paired specimen testing using the following approaches.

Justification: Detecting confirmed or suspected SARS-CoV-2 reinfections is critical to public health control and related risk assessments. The possibility of reinfection could present challenges to controlling viral transmission within communities or within specific vulnerable populations. A better understanding of reinfection and the immune response to SARS-CoV-2 is also needed to inform vaccine planning efforts.

Intended use of study findings: Findings on the likelihood of reinfection will be used to guide future public health surveillance and prevention guidance for COVID-19. Additionally, confirmed or suspected SARS-CoV-2 reinfection case detection can inform future research into SARS-CoV-2 host immunity and vaccine development.

Study design: This protocol describes the use of public health surveillance of suspected SARS-CoV-2 reinfection cases to systematically investigate these cases and guide public health response. The protocol can be used to investigate both passively reported cases and those detected through routine queries on case-based surveillance data in which individuals with multiple test results are tracked over time. The protocol includes diagnostic testing of available specimens from distinct episodes of SARS-CoV-2 RT-PCR positivity as well as laboratory guidance and quality standards for genomic analysis.

Objectives: 1. Determine the frequency at which SARS-CoV-2 reinfection occurs among persons who appear to have recovered clinically from COVID-19. 2. Characterize suspected SARS-CoV-2 reinfection cases and resulting laboratory evidence to better understand the natural history of SARS-CoV-2 infection and guide public health response. 3. Determine the time interval from initial illness to reinfection.

Questions: What is the frequency with which SARS-CoV-2 reinfection occurs in humans? What is the interval between initial infection and reinfection, and what is the clinical course? Among confirmed reinfection cases, what is the duration of RT-PCR positivity and shedding of replication-competent virus? What is the serologic response to reinfection?

General approach: Descriptive epidemiology paired with genomic testing might be used to identify or support SARS-CoV-2 reinfection. Serial antibody determination and evidence of active viral replication might be used to provide additional support for and further characterize SARS-CoV-2 reinfections.

Procedures/Methods

DESIGN

Statement of purpose: This toolkit is designed to provide state and local health departments with the tools needed to investigate suspected cases of SARS-CoV-2 reinfection.

How investigational design meets objectives: This toolkit can be used in conjunction with surveillance (passive or active) for suspected cases of SARS-CoV-2 reinfection. Once the study population is identified, chart abstraction and reviews of existing surveillance reporting will be used to characterize suspected cases. Additionally, paired specimens might undergo confirmatory RT-PCR, viral culture, sgmRNA, and genomic sequencing to provide evidence of reinfection.

Description of risks: This research involves little to no risk to participants. Adherence to the HIPAA Privacy Rule and deidentification of collected data will ensure participant anonymity. If additional nasal wash specimens are collected, adverse effects are expected to be mild but could include nosebleeds and nasal irritation. If additional serum is collected, adverse effects are expected to be mild but could include hematoma or bruising. There is also minimal risk to the medical professionals. For sub-studies pursuing additional specimen collection we recommend following universal precautions and COVID-19 guidance on specimen collection and transport (Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19).

Description of anticipated benefits to the research participant: We anticipate that research participants will benefit from the improved COVID-19 prevention guidelines that will result from this research.

Description of the potential risks to anticipated benefit ratio: The potential risks posed by specimen collection are outweighed by the societal and individual benefit of enhanced surveillance and improved prevention guidelines that could reduce transmission of SARS-CoV-2 within communities.

STUDY POPULATION

Description and source of study population: The study population can include all individuals with a suspected or confirmed case of COVID-19 within the surveillance catchment area or the health department’s jurisdiction.

Investigative criteria:

Prioritize persons with detected SARS-CoV-2 RNA ≥90 days since first SARS-CoV-2 infection:

Persons with detected SARS-CoV-2 RNA* ≥90 days after the first detection of SARS-CoV-2 RNA, whether or not symptoms were present

AND

Paired respiratory specimens (one from each infection episode) are available

*If detected by RT-PCR, only include if Ct value <33 or if Ct value unavailable

Consider persons with COVID-19–like symptoms and detection of SARS-CoV-2 RNA 45–89 days since first SARS-CoV-2 infection:

Persons with detection of SARS-CoV-2 RNA* ≥45 days after the first detection of SARS-CoV-2 RNA

AND

With a symptomatic second episode and no obvious alternate etiology for COVID-19–like symptoms OR close contact with a person known to have laboratory-confirmed COVID-19

AND

Paired respiratory specimens (one from each infection episode) are available

*If detected by RT-PCR, only include if Ct value <33 or if Ct value unavailable

Adaptation considerations:

  • If resources are limited, further prioritize the sampling of persons in high-risk groups (e.g. healthcare workers).
  • If investigating suspected reinfection cases among severely immunocompromised persons, consider a prospective study dedicated to this population, as results will not be generalizable to the general population.

Participant exclusion criteria:

  • Laboratory specimen from either first or second illness episode is unavailable.

Estimated number of participants: The estimated monthly enrollment is expected to vary by jurisdiction, duration of local outbreak intensity, and referral testing operational factors. Consider taking these factors, as well as prior number of suspected SARS-CoV-2 cases reported, into account during local protocol adaptation.

Sampling: No a priori sampling will be undertaken; instead all suspected cases reported will be investigated per protocol. When necessary, eligibility criteria may be narrowed per adaptation considerations provided in this common investigation protocol.

Recruitment and Enrollment: Options for enrollment are as follow:

  1. Passive surveillance: Cases reported to the health department that meet eligibility criteria
  2. Active surveillance: Routinely analyze RT-PCR data with individual unique IDs over time to identify those with recurrent positive tests beyond the given time intervals
  3. Once cases are identified, optionally enroll case-patients in a sub-study to characterize the clinical course of reinfection events.
  4. If interested in investigating duration of viral shedding, presence of replication-competent virus, and serologic response to suspected reinfection, optionally enroll case-patients in a sub-study to collect serial respiratory and serum specimens.

Description and justification of reimbursements or incentives that will be used: Any reimbursements or incentives provided to participants are at the discretion of the institution using this protocol.

Statement of extra costs to participants due to involvement in the study: Participants may incur extra costs in the form of travel expenses and time lost to interviews. These costs will only be incurred if participants consent to the collection of additional nasal specimens and follow up interviews.

Procedures for implementing and documenting informed consent: Whenever appropriate, obtain informed consent from participants that require interviews for data collection, complete 14-day symptom logs, or enroll them in a sub-study for subsequent respiratory and serum specimen collection.

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