Medicine and Vaccine Research
Antibody Responses in People with Past Natural Covid-19 Infection: Neutralizing antibody responses in previously infected participants who received one dose of vaccine was higher than in previously uninfected patients who received two doses.
Whether or not persons who have already been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be vaccinated is unclear. Only a few studies have shown that vaccinees who were previously infected with SARS-CoV-2 had a significantly higher antibody response than previously uninfected vaccinees.1-4 In an observational cohort study, we enrolled 100 health care workers, including 38 (9 men and 29 women) with a documented history of SARS-CoV-2 infection (mean duration between infection and vaccination, 111 days).
The mean age of these previously infected participants was 35.1 years (95% confidence interval [CI], 31.7 to 38.6). Our study also included 62 participants (25 men and 37 women) who had not been previously infected. The mean age of those participants was 44.7 years (95% CI, 41.0 to 47.6).
Both groups of participants received the messenger RNA vaccine BNT162b2 (Pfizer–BioNTech). Serum samples were obtained from the previously infected participants 10 days after the administration of the first dose and from the previously uninfected participants 10 days after the administration of the second dose. Thereafter, all the participants were screened for the presence of specific anti–SARS-CoV-2 spike IgG by means of a chemiluminescence microparticle immunoassay.
No significant difference in circulating anti-spike IgG antibody titers was observed between the samples from previously infected participants (mean level, 20,120 arbitrary units per milliliter; 95% CI, 16,400 to 23,800) and those from previously uninfected participants (mean level, 22,639 arbitrary units per milliliter; 95% CI, 19,400 to 25,900) (median levels are shown in Figure 1A). Circulating anti-spike IgG antibodies were not detected in only one previously infected participant; that participant did not have an antibody response to natural infection with SARS-CoV-2.
The same serum samples were also analyzed for the presence of specific anti–SARS-CoV-2 neutralizing antibodies. We observed a difference in levels of neutralizing antibodies between samples from the previously infected participants (geometric mean titer, 569; 95% CI, 467 to 670) and those from the previously uninfected participants (geometric mean titer, 118; 95% CI, 85 to 152) (P<0.001) (median levels are shown in Figure 1B). No substantial differences were noted between the titers from the previously infected and the previously uninfected participants according to age (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org) or sex (data not shown).
The previously infected participants were categorized into three groups according to the time that had elapsed from infection to vaccination: 1 to 2 months (8 participants), more than 2 months to 3 months (17 participants), and more than 3 months (12 participants). The previously infected patient in whom circulating anti-spike IgG antibodies were not detected was not included in this categorization. The circulating IgG mean titers differed between the group vaccinated at 1 to 2 months and the group vaccinated at more than 2 months to 3 months after natural infection (mean level, 15,837 arbitrary units per milliliter [95% CI, 11,265 to 20,410] vs. 21,450 arbitrary units per milliliter [95% CI, 15,377 to 27,523]) (median levels are shown in Figure 1C); however, because the number of participants was limited, a real distinction cannot be made. No further significant difference was observed between the group of participants vaccinated at more than 2 months to 3 months and the group of those vaccinated more than 3 months after infection (mean level, 21,090 arbitrary units per milliliter [95% CI, 14,702 to 27,477]).
The differences among the three groups were more evident with respect to levels of neutralizing antibodies, with geometric mean titers ranging from 437 (95% CI, 231 to 643) in participants vaccinated 1 to 2 months after infection to 559 (95% CI, 389 to 730) in those vaccinated more than 2 months to 3 months after infection to 694 (95% CI, 565 to 823) in those vaccinated more than 3 months after infection (median levels are shown in Figure 1D). Although these findings indicate that the booster response was more efficacious when the vaccine was administered more than 3 months after infection, not enough information is available to draw a definitive conclusion.
The most remarkable finding of this study was the significantly lower neutralizing antibody titer after administration of a second dose of vaccine in previously uninfected patients than the titer after only a single dose of vaccine in previously infected participants. It is unclear how the neutralizing antibody titers influence the ability of the host to transmit the virus. These findings provide evidence that after the administration of a single dose of vaccine, the humoral response against SARS-CoV-2 in persons with a history of SARS-CoV-2 infection is greater than the response in previously uninfected participants who have received a second dose.
Length of Time A Person With Covid Symptoms Should Isolate The CDC recommends isolation precautions for 10 days after symptom onset, with extension to 20 days for immunocompromised patients or those with severe illness.
A 24-year-old woman with no relevant medical history presented to the emergency department with a 1-week history of cough and shortness of breath. She stated that she had not had any contact with people who were sick but had recently attended a small event. She reported no fever, diarrhea, or loss of taste or smell. On physical examination, she was found to have hypoxemia, with an oxygen saturation of 88%, and crackles were heard on lung auscultation. A chest radiograph showed bilateral interstitial opacities, and a polymerase-chain-reaction (PCR) assay was positive for SARS-CoV-2. She was given supplemental oxygen, delivered by nasal cannula at 2 liters per minute, and was placed in an isolation observation unit overnight for monitoring.
The next day, she continued to require oxygen and was admitted to a ward bed. Her oxygen requirements increased, and she was given supplemental oxygen at a rate of 15 liters per minute through a nonrebreather mask and was admitted to the intensive care unit (ICU). Her condition improved over the course of the week, and her need for supplemental oxygen decreased. The remainder of her course was uneventful, and she was transferred back to a ward bed.
It has now been 1 week since her admission to the hospital, and discharge planning has started. The patient plans to go home to stay with her parents, both of whom are over the age of 65 years, while she recuperates. She is concerned about the risk of transmission of SARS-CoV-2 to her parents. Her father is taking immunosuppressive medication after recent kidney transplantation. She has requested that PCR testing be performed again on a repeat nasopharyngeal swab. The PCR test is performed, and the result is positive.
You must advise the patient about the risk of transmitting the virus to her parents, given the time since the onset of Covid-19 symptoms and the positive repeat PCR test.
Treatment Options
Which one of the following approaches would you take? Base your choice on the literature, your own experience, published guidelines, and other information sources.
-
Recommend continued isolation.
-
Reassure the patient of the low risk of transmission.
To aid in your decision making, each of these approaches is defended in a short essay by an expert in the field. Given your knowledge of the issue and the points made by the experts, which approach would you choose?
- Option 1: Recommend Continued Isolation
- Option 2: Reassure the Patient of the Low Risk of Transmission
Recommend Continued Isolation
Recommendations on the duration of isolation for patients with Covid-19 continue to evolve with increased understanding of SARS-CoV-2 transmission dynamics. Early in the Covid-19 pandemic, recommendations from the Centers for Disease Control and Prevention (CDC) included discontinuing isolation when there was clinical improvement and a negative molecular SARS-CoV-2 test. This recommendation was replaced by a time-based approach (rather than a test-based one) when it became apparent that shedding of nonviable SARS-CoV-2 RNA in the upper respiratory tract can continue for days to weeks after recovery from illness.1 Early, albeit small studies showed that SARS-CoV-2 detected by PCR in respiratory specimens beyond day 10 after the onset of symptoms did not grow in cell culture and was probably not transmissible.2,3 Large population-based studies conducted by CDC South Korea indicate that the infectious potential of SARS-CoV-2 declines after the first week following symptom onset, irrespective of resolution of symptoms.4
However, a few studies have recently challenged this concept. One study showed viable virus by in vitro growth in cell culture in 14% of patients (4 of 29) with persistent positive SARS-CoV-2 PCR tests from upper respiratory specimens obtained after the first week following the initial positive PCR test; one patient was never hospitalized, and one had been hospitalized with mild symptoms.5 Complete viral genome sequencing indicated that these cases represented the same infection rather than reinfection. Age, immunocompromised status, and severe illness have been associated with prolonged SARS-CoV-2 RNA shedding1; however, data are insufficient regarding factors associated with prolonged shedding of viable SARS-CoV-2. One recent study showed that some patients with immunosuppression after treatment for cancer could shed viable SARS-CoV-2 for at least 2 months.6 A study of 129 severe cases of Covid-19 showed that the probability of detecting viable virus beyond day 15 after symptom onset was 5% or less.7
The CDC currently recommends isolation precautions for 10 days after symptom onset (with fever resolution lasting at least 24 hours without the use of fever-reducing medications), with extension to 20 days for immunocompromised patients or those with severe illness. The patient described in the clinical vignette had severe infection according to the World Health Organization severity scale and CDC criteria; thus, continuing isolation for a total of 20 days seems reasonable and in accordance with current evidence. No studies to date have reported person-to-person transmission occurring from the observed late shedding of viable SAR-CoV-2; thus, it may be reasonable to customize decisions regarding duration of isolation on the basis of individual circumstances. In the current case, a household member is a kidney transplant recipient, a condition in which Covid-19 infection is associated with high morbidity and mortality, which further justifies a 20-day isolation period.
Repeat SARS-CoV-2 PCR testing to determine the duration of isolation should not be recommended for this patient because, as noted, a positive PCR test does not mean that she is infectious, and viral tissue culture is not available to assess for viable virus in clinical laboratories. Repeat PCR testing can result in unnecessarily prolonged isolation and anxiety for patients and medical teams. Public awareness of the shortcomings of Covid-19 diagnostic tests and the distinction between shedding of viral RNA and viable virus is essential to ensure that patients and health care workers are comfortable with our current approach to isolation precautions for patients with Covid-19.
Antibody Responses in People with Past Natural Covid-19 Infection: Neutralizing antibody responses in previously infected participants who received one dose of vaccine was higher than in previously uninfected patients who received two doses.
Neutralizing antibody responses in previously infected participants who received one dose of vaccine was higher than in previously uninfected patients who received two doses.
Whether or not persons who have already been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be vaccinated is unclear. Only a few studies have shown that vaccinees who were previously infected with SARS-CoV-2 had a significantly higher antibody response than previously uninfected vaccinees.1-4 In an observational cohort study, we enrolled 100 health care workers, including 38 (9 men and 29 women) with a documented history of SARS-CoV-2 infection (mean duration between infection and vaccination, 111 days).
The mean age of these previously infected participants was 35.1 years (95% confidence interval [CI], 31.7 to 38.6). Our study also included 62 participants (25 men and 37 women) who had not been previously infected. The mean age of those participants was 44.7 years (95% CI, 41.0 to 47.6).
Both groups of participants received the messenger RNA vaccine BNT162b2 (Pfizer–BioNTech). Serum samples were obtained from the previously infected participants 10 days after the administration of the first dose and from the previously uninfected participants 10 days after the administration of the second dose. Thereafter, all the participants were screened for the presence of specific anti–SARS-CoV-2 spike IgG by means of a chemiluminescence microparticle immunoassay.
No significant difference in circulating anti-spike IgG antibody titers was observed between the samples from previously infected participants (mean level, 20,120 arbitrary units per milliliter; 95% CI, 16,400 to 23,800) and those from previously uninfected participants (mean level, 22,639 arbitrary units per milliliter; 95% CI, 19,400 to 25,900) (median levels are shown in Figure 1A). Circulating anti-spike IgG antibodies were not detected in only one previously infected participant; that participant did not have an antibody response to natural infection with SARS-CoV-2.
The same serum samples were also analyzed for the presence of specific anti–SARS-CoV-2 neutralizing antibodies. We observed a difference in levels of neutralizing antibodies between samples from the previously infected participants (geometric mean titer, 569; 95% CI, 467 to 670) and those from the previously uninfected participants (geometric mean titer, 118; 95% CI, 85 to 152) (P<0.001) (median levels are shown in Figure 1B). No substantial differences were noted between the titers from the previously infected and the previously uninfected participants according to age (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org) or sex (data not shown).
The previously infected participants were categorized into three groups according to the time that had elapsed from infection to vaccination: 1 to 2 months (8 participants), more than 2 months to 3 months (17 participants), and more than 3 months (12 participants). The previously infected patient in whom circulating anti-spike IgG antibodies were not detected was not included in this categorization. The circulating IgG mean titers differed between the group vaccinated at 1 to 2 months and the group vaccinated at more than 2 months to 3 months after natural infection (mean level, 15,837 arbitrary units per milliliter [95% CI, 11,265 to 20,410] vs. 21,450 arbitrary units per milliliter [95% CI, 15,377 to 27,523]) (median levels are shown in Figure 1C); however, because the number of participants was limited, a real distinction cannot be made. No further significant difference was observed between the group of participants vaccinated at more than 2 months to 3 months and the group of those vaccinated more than 3 months after infection (mean level, 21,090 arbitrary units per milliliter [95% CI, 14,702 to 27,477]).
The differences among the three groups were more evident with respect to levels of neutralizing antibodies, with geometric mean titers ranging from 437 (95% CI, 231 to 643) in participants vaccinated 1 to 2 months after infection to 559 (95% CI, 389 to 730) in those vaccinated more than 2 months to 3 months after infection to 694 (95% CI, 565 to 823) in those vaccinated more than 3 months after infection (median levels are shown in Figure 1D). Although these findings indicate that the booster response was more efficacious when the vaccine was administered more than 3 months after infection, not enough information is available to draw a definitive conclusion.
The most remarkable finding of this study was the significantly lower neutralizing antibody titer after administration of a second dose of vaccine in previously uninfected patients than the titer after only a single dose of vaccine in previously infected participants. It is unclear how the neutralizing antibody titers influence the ability of the host to transmit the virus. These findings provide evidence that after the administration of a single dose of vaccine, the humoral response against SARS-CoV-2 in persons with a history of SARS-CoV-2 infection is greater than the response in previously uninfected participants who have received a second dose.
Length of Time A Person With Covid Symptoms Should Isolate The CDC recommends isolation precautions for 10 days after symptom onset, with extension to 20 days for immunocompromised patients or those with severe illness.
The CDC recommends isolation precautions for 10 days after symptom onset, with extension to 20 days for immunocompromised patients or those with severe illness.
A 24-year-old woman with no relevant medical history presented to the emergency department with a 1-week history of cough and shortness of breath. She stated that she had not had any contact with people who were sick but had recently attended a small event. She reported no fever, diarrhea, or loss of taste or smell. On physical examination, she was found to have hypoxemia, with an oxygen saturation of 88%, and crackles were heard on lung auscultation. A chest radiograph showed bilateral interstitial opacities, and a polymerase-chain-reaction (PCR) assay was positive for SARS-CoV-2. She was given supplemental oxygen, delivered by nasal cannula at 2 liters per minute, and was placed in an isolation observation unit overnight for monitoring.
The next day, she continued to require oxygen and was admitted to a ward bed. Her oxygen requirements increased, and she was given supplemental oxygen at a rate of 15 liters per minute through a nonrebreather mask and was admitted to the intensive care unit (ICU). Her condition improved over the course of the week, and her need for supplemental oxygen decreased. The remainder of her course was uneventful, and she was transferred back to a ward bed.
It has now been 1 week since her admission to the hospital, and discharge planning has started. The patient plans to go home to stay with her parents, both of whom are over the age of 65 years, while she recuperates. She is concerned about the risk of transmission of SARS-CoV-2 to her parents. Her father is taking immunosuppressive medication after recent kidney transplantation. She has requested that PCR testing be performed again on a repeat nasopharyngeal swab. The PCR test is performed, and the result is positive.
You must advise the patient about the risk of transmitting the virus to her parents, given the time since the onset of Covid-19 symptoms and the positive repeat PCR test.
Treatment Options
Which one of the following approaches would you take? Base your choice on the literature, your own experience, published guidelines, and other information sources.
-
Recommend continued isolation.
-
Reassure the patient of the low risk of transmission.
To aid in your decision making, each of these approaches is defended in a short essay by an expert in the field. Given your knowledge of the issue and the points made by the experts, which approach would you choose?
- Option 1: Recommend Continued Isolation
- Option 2: Reassure the Patient of the Low Risk of Transmission
Recommend Continued Isolation
Recommendations on the duration of isolation for patients with Covid-19 continue to evolve with increased understanding of SARS-CoV-2 transmission dynamics. Early in the Covid-19 pandemic, recommendations from the Centers for Disease Control and Prevention (CDC) included discontinuing isolation when there was clinical improvement and a negative molecular SARS-CoV-2 test. This recommendation was replaced by a time-based approach (rather than a test-based one) when it became apparent that shedding of nonviable SARS-CoV-2 RNA in the upper respiratory tract can continue for days to weeks after recovery from illness.1 Early, albeit small studies showed that SARS-CoV-2 detected by PCR in respiratory specimens beyond day 10 after the onset of symptoms did not grow in cell culture and was probably not transmissible.2,3 Large population-based studies conducted by CDC South Korea indicate that the infectious potential of SARS-CoV-2 declines after the first week following symptom onset, irrespective of resolution of symptoms.4
However, a few studies have recently challenged this concept. One study showed viable virus by in vitro growth in cell culture in 14% of patients (4 of 29) with persistent positive SARS-CoV-2 PCR tests from upper respiratory specimens obtained after the first week following the initial positive PCR test; one patient was never hospitalized, and one had been hospitalized with mild symptoms.5 Complete viral genome sequencing indicated that these cases represented the same infection rather than reinfection. Age, immunocompromised status, and severe illness have been associated with prolonged SARS-CoV-2 RNA shedding1; however, data are insufficient regarding factors associated with prolonged shedding of viable SARS-CoV-2. One recent study showed that some patients with immunosuppression after treatment for cancer could shed viable SARS-CoV-2 for at least 2 months.6 A study of 129 severe cases of Covid-19 showed that the probability of detecting viable virus beyond day 15 after symptom onset was 5% or less.7
The CDC currently recommends isolation precautions for 10 days after symptom onset (with fever resolution lasting at least 24 hours without the use of fever-reducing medications), with extension to 20 days for immunocompromised patients or those with severe illness. The patient described in the clinical vignette had severe infection according to the World Health Organization severity scale and CDC criteria; thus, continuing isolation for a total of 20 days seems reasonable and in accordance with current evidence. No studies to date have reported person-to-person transmission occurring from the observed late shedding of viable SAR-CoV-2; thus, it may be reasonable to customize decisions regarding duration of isolation on the basis of individual circumstances. In the current case, a household member is a kidney transplant recipient, a condition in which Covid-19 infection is associated with high morbidity and mortality, which further justifies a 20-day isolation period.
Repeat SARS-CoV-2 PCR testing to determine the duration of isolation should not be recommended for this patient because, as noted, a positive PCR test does not mean that she is infectious, and viral tissue culture is not available to assess for viable virus in clinical laboratories. Repeat PCR testing can result in unnecessarily prolonged isolation and anxiety for patients and medical teams. Public awareness of the shortcomings of Covid-19 diagnostic tests and the distinction between shedding of viral RNA and viable virus is essential to ensure that patients and health care workers are comfortable with our current approach to isolation precautions for patients with Covid-19.