What reinfections mean for COVID-19
Authors: Akiko Iwasaki
Journal: The Lancet Infectious Diseases (2020)

One of the key questions in predicting the course of the COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is how well and how long the immune responses protect the host from reinfection. For some viruses, the first infection can provide lifelong immunity; for seasonal coronaviruses, protective immunity is short-lived.1Edridge AWD Kaczorowska J Hoste ACR et al.Seasonal coronavirus protective immunity is short-lasting.Nat Med. 2020; (published online Sept 14.)https://doi.org/10.1038/s41591-020-1083-1Crossref PubMed Scopus (474) Google Scholar In The Lancet Infectious Diseases, Richard L Tillett and colleagues describe the first confirmed case of SARS-CoV-2 reinfection in the USA.2Tillett RL Sevinsky JR Hartley PD et al.Genomic evidence for reinfection with SARS-CoV-2: a case study.Lancet Infect Dis. 2020; (published online Oct 12.)https://doi.org/10.1016/S1473-3099(20)30764-7Summary Full Text Full Text PDF PubMed Scopus (525) Google Scholar A 25-year-old man from the US state of Nevada, who had no known immune disorders, had PCR-confirmed SARS-CoV-2 infection in April, 2020 (cycle threshold [Ct] value 35·24; specimen A). He recovered in quarantine, testing negative by RT-PCR at two consecutive timepoints thereafter. However, 48 days after the initial test, the patient tested positive again by RT-PCR (Ct value 35·31; specimen B). Viral genome sequencing showed that both specimens A and B belonged to clade 20C, a predominant clade seen in northern Nevada. However, the genome sequences of isolates from the first infection (specimen A) and reinfection (specimen B) differed significantly, making the chance of the virus being from the same infection small. What is worrisome is that SARS-CoV-2 reinfection resulted in worse disease than did the first infection, requiring oxygen support and hospitalisation. The patient had positive antibodies after the reinfection, but whether he had pre-existing antibody after the first infection is unknown (table).TableCharacteristics associated with reinfection with SARS-CoV-2SexAge (years)First infection (Ct)Second infection (Ct)Intervening period (days)Antibody after first infectionAntibody after reinfectionHong Kong3To KK-W Hung IF-N Ip JD et al.COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing.Clin Infect Dis. 2020; (published online Aug 25.)https://doi.org/10.1093/cid/ciaa1275Crossref Scopus (433) Google ScholarMale33Mild (N/A)Asymptomatic (27)142NegativeIgG+Nevada, USA2Tillett RL Sevinsky JR Hartley PD et al.Genomic evidence for reinfection with SARS-CoV-2: a case study.Lancet Infect Dis. 2020; (published online Oct 12.)https://doi.org/10.1016/S1473-3099(20)30764-7Summary Full Text Full Text PDF PubMed Scopus (525) Google ScholarMale25Mild (35)Hospitalised (35)48N/AIgM+ and IgG+Belgium4Van Elslande J Vermeersch P Vandervoort K et al.Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain.Clin Infect Dis. 2020; (published online Sept 5.)https://doi.org/10.1093/cid/ciaa1330Crossref PubMed Scopus (151) Google ScholarFemale51Mild (26–27)Milder (33)93N/AIgG+Ecuador5Prado-Vivar B Becerra-Wong M Guadalupe JJ et al.COVID-19 re-infection by a phylogenetically distinct SARS-CoV-2 variant, first confirmed event in South America.SSRN. 2020; (published online Sept 8.) (preprint)https://doi.org/10.2139/ssrn.3686174Crossref Google ScholarMale46Mild (37)Worse (N/A)63IgM– and IgG–IgM+ and IgG+Data were obtained Sept 14, 2020, for reinfection cases confirmed by viral genome sequences. Ct=cycle threshold. N/A=not available. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. Open table in a new tab Data were obtained Sept 14, 2020, for reinfection cases confirmed by viral genome sequences. Ct=cycle threshold. N/A=not available. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. This case report adds to rapidly growing evidence of COVID-19 reinfection, in which viral genomic sequences were used to confirm infections by distinct isolates of SARS-CoV-2. What do reinfection cases mean for public health and vaccination endeavors to stop the COVID-19 pandemic? Do reinfections occur because of a scant antibody response after first infection? Of the four reinfection cases reported to date, none of the individuals had known immune deficiencies. Currently, only two individuals had serological data from the first infection and one had pre-existing antibody (IgM) against SARS-CoV-2. Because of the wide range of serological testing platforms used across the globe, it is impossible to compare results from one assay to another. For example, antibody reactivity to nucleocapsid protein indicates previous exposure to SARS-CoV-2 but not whether antibodies that can block infection (anti-spike) are present. Also, antibody levels are highly dependent on the timing after exposure. The key goal for the future is to ascertain the level and specificity of antibody to spike protein at the time of reinfection, to determine immune correlate of protection. Does immunity protect an individual from disease on reinfection? The answer is not necessarily, because patients from Nevada and Ecuador had worse disease outcomes at reinfection than at first infection. It is important to keep in mind that the reinfection cases in general are being picked up because of symptoms and are biased towards detection of symptomatic cases. Due to the paucity of broad testing and surveillance, we do not know how frequently reinfection occurs among individuals who recovered from their first infection. Asymptomatic reinfection cases can only be picked up by routine community testing or at an airport, for example,3To KK-W Hung IF-N Ip JD et al.COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing.Clin Infect Dis. 2020; (published online Aug 25.)https://doi.org/10.1093/cid/ciaa1275Crossref Scopus (433) Google Scholar and we are probably severely underestimating the number of asymptomatic reinfections. Why do some reinfections result in milder disease,3To KK-W Hung IF-N Ip JD et al.COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing.Clin Infect Dis. 2020; (published online Aug 25.)https://doi.org/10.1093/cid/ciaa1275Crossref Scopus (433) Google Scholar, 4Van Elslande J Vermeersch P Vandervoort K et al.Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain.Clin Infect Dis. 2020; (published online Sept 5.)https://doi.org/10.1093/cid/ciaa1330Crossref PubMed Scopus (151) Google Scholar whereas others are more severe?2Tillett RL Sevinsky JR Hartley PD et al.Genomic evidence for reinfection with SARS-CoV-2: a case study.Lancet Infect Dis. 2020; (published online Oct 12.)https://doi.org/10.1016/S1473-3099(20)30764-7Summary Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 5Prado-Vivar B Becerra-Wong M Guadalupe JJ et al.COVID-19 re-infection by a phylogenetically distinct SARS-CoV-2 variant, first confirmed event in South America.SSRN. 2020; (published online Sept 8.) (preprint)https://doi.org/10.2139/ssrn.3686174Crossref Google Scholar Further investigation is needed of pre-existing immune responses before second exposure, and viral inoculum load. Does infection by different viral isolates mean we need a vaccine for each type? While differences in the viral genome sequence of the various isolates are a great way to know if an individual is reinfected (ruling out reactivation of lingering virus infection), it does not indicate that the second infection was due to immune evasion. There is currently no evidence that a SARS-CoV-2 variant has emerged as a result of immune evasion. For now, one vaccine will be sufficient to confer protection against all circulating variants.6Dearlove B Lewitus E Bai H et al.A SARS-CoV-2 vaccine candidate would likely match all currently circulating variants.Proc Natl Acad Sci USA. 2020; 117: 23652-23662Crossref PubMed Scopus (144) Google Scholar Furthermore, reinfection by a distinct viral variant from the original virus does not imply immune escape. Does immunity prevent transmission from those who are reinfected? The Ct value of PCR correlates with viral load, and low Ct values (high viral load) might indicate infectiousness of the individual. Although Ct values can vary substantially between various tests and laboratories, in one study, samples with Ct values greater than 35 were only 8% positive for cultivable virus.7Singanayagam A Patel M Charlett A et al.Duration of infectiousness and correlation with RT-PCR cycle threshold values in cases of COVID-19, England, January to May 2020.Euro Surveill. 2020; 252001483Crossref Scopus (598) Google Scholar A good proxy for infectiousness can be obtained through viral plaque assays that measure the infectious virus. However, these assays require biosafety level 3 facilities and are labour intensive, and the assays are not routinely done in clinical laboratories. Since some reinfection cases had Ct values less than 35,3To KK-W Hung IF-N Ip JD et al.COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing.Clin Infect Dis. 2020; (published online Aug 25.)https://doi.org/10.1093/cid/ciaa1275Crossref Scopus (433) Google Scholar, 4Van Elslande J Vermeersch P Vandervoort K et al.Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain.Clin Infect Dis. 2020; (published online Sept 5.)https://doi.org/10.1093/cid/ciaa1330Crossref PubMed Scopus (151) Google Scholar infectious virus might have been harboured in the nasal cavity. Thus, reinfection cases tell us that we cannot rely on immunity acquired by natural infection to confer herd immunity; not only is this strategy lethal for many but also it is not effective. Herd immunity requires safe and effective vaccines and robust vaccination implementation. As more cases of reinfection surface, the scientific community will have the opportunity to understand better the correlates of protection and how frequently natural infections with SARS-CoV-2 induce that level of immunity. This information is key to understanding which vaccines are capable of crossing that threshold to confer individual and herd immunity. I declare no competing interests. Genomic evidence for reinfection with SARS-CoV-2: a case studyGenetic discordance of the two SARS-CoV-2 specimens was greater than could be accounted for by short-term in vivo evolution. These findings suggest that the patient was infected by SARS-CoV-2 on two separate occasions by a genetically distinct virus. Thus, previous exposure to SARS-CoV-2 might not guarantee total immunity in all cases. All individuals, whether previously diagnosed with COVID-19 or not, should take identical precautions to avoid infection with SARS-CoV-2. The implications of reinfections could be relevant for vaccine development and application. Full-Text PDF Correction to Lancet Infect Dis 2020; published online Oct 12. https://doi.org/10.1016/S1473-3099(20)30783-0Iwasaki A. What reinfections mean for COVID-19. Lancet Infect Dis 2020; published online Oct 12. https://doi.org/10.1016/S1473-3099(20)30783-0—In the table of this Comment, for the Ecuador patient, data in the Antibody after first infection column should be IgM+ IgG–. This correction has been made to the online version as of Nov 6, 2020, and will be made to the printed Comment. Full-Text PDF Ct values and infectivity of SARS-CoV-2 on surfacesAkiko Iwasaki1 raises the important question of whether a person with a positive PCR test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is automatically infectious or infectious only if the cycle threshold (Ct) is below a certain value (eg, <35). The same question should be asked for other potential sources of viral spread, such as inanimate surfaces. Full-Text PDF Realising the potential of SARS-CoV-2 vaccines—a long shot?The race to develop safe, effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has produced impressive results. As of Jan 18, 2021, 64 vaccines were in clinical development according to the WHO COVID-19 candidate vaccine database. Phase 3 data for two RNA vaccines, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna), and the adenovirus-vectored vaccine ChAdOx1 nCoV-19 (Oxford University/AstraZeneca) have been published in peer-reviewed journals, and further phase 3 reports are expected imminently. Full-Text PDF