Insights About Reinfection and Immunization

661 views 4 05/02/2020 05/03/2020 and

How long does the immunity last after infections with coronaviruses? Is it possible to get reinfected? 

As of now, one of the hospital discharge criterias for COVID-19 infection is that with at least a one-day interval, two repetitive RT-PCR tests done on throat swabs have turned up negative. This method of testing is currently questioned because of its sufficiently high rate of false negatives, thus raising questions as to the true possibility of reinfection versus the test’s more probable inability to detect a virus’ presence several days after symptoms have stopped and viral shedding is low but still present. Here is the pertinent data about reinfection and immunization pertaining to SARS-CoV, MERS-CoV, coronaviruses in general and the novel SARS-CoV-2.

 

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV, 2002)

In humans, antibodies levels seem to be maintained for about 2 years and wane afterwards suggesting a certain risk to reinfection. A study found that antibodies (IgG) are maintained in ≥ 90% of patients after 2 years. However, there was a significant decrease of IgG titers after 3 years.1 Another study found similar results, finding detectable IgG in 88.2% of patients after 2 years as well as detectable but markedly decreasing neutralizing antibodies.2 In another study, 6 years after the primary infection, very low levels of IgG in 8.7% of recovered SARS patients and undetectable memory B cells levels have been found.  However, about 60.9% of these patients have maintained specific memory T cell response. Response was higher in those who had more severe manifestation during SARS infection.3 The significance of these results are unclear but previous studies have suggested that protective immunity from memory T cells is only effective if it is in concert with memory B cells.4

In animal models, only short-term studies have been realized. Ferrets mounted an effective response to reinfection 30 days after the primary infection. A second peak of neutralizing antibody titer, with restricted virus replication and less symptoms and lung pathology, has been shown in these animals. Neutralizing antibody titer started to decrease about 15 days after reinfection.5 Mice seemed to be protected against reinfection 28 days after the primary infection. Indeed, they had higher neutralizing antibody titer when compared to control group and undetectable virus titer with subsequent virus challenge.6

 

Middle East Respiratory Syndrome Coronavirus (MERS-CoV, 2012)

In humans, one study of 7 patients has found decreasing but persistent neutralizing antibodies in 86% of patients 34 months after the primary infection when compared to 13 months after infection. Their results also suggest that more severe symptoms increase the likelihood of having remaining antibodies. However, this last statement needs more supporting data.7

In rabbits inoculated with MERS-CoV, acquired neutralizing antibodies provided some protection against the severity of the reinfection 8 weeks later regarding the inflammation in the lungs. However, those who have not developed neutralizing antibodies had an enhanced inflammation reaction to the reinfection. Rabbits who have received a higher dose of virus at first place had lower levels of antigens during the secondary infection.8

In camels, the natural hosts of MERS-CoV, an observational longitudinal study has shown that previously infected animals can be reinfected. Thus, prior infection does not provide complete immunity against MERS-CoV.9

 

Other coronaviruses

In the past, human studies with coronavirus 229E have demonstrated that antibody concentrations start decreasing approximately two weeks after inoculation and that while still being increased one year post inoculation, they do not prevent reinfection when subjects are submitted to re-challenge with the homologous virus, although further results show a lesser extent of infection and a shorter duration of viral shedding. One year post-primary infection, a small amount of antibody persists in some, while in others, no antibody concentration is detected.10

 

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2, 2019) / COronaVIrus Disease 2019 (COVID-19) 

What studies show so far:

  • In COVID-19 infected patients that have tested negative to two RT-PCR tests from throat swabs at discharge, RT-PCR results of rectal and/or throat swabs can come back positive 7-11 days after discharge, without any symptoms and no changes in chest CT scans, thus making it more likely that results at discharge were falsely negative.11
  • A patient with COVID-19 from a case-series study had a positive RT-PCR 22 days after being discharged from the hospital, with a decrease in initial symptoms, an improved CT scan and normal blood tests, indicating that the patients’ positive nucleic acid test after discharge was most likely due to incomplete viral clearance.12
  • Viral shedding from the digestive system might last longer than from the respiratory tract, making it pertinent to raise the possibility of adding rectal swab specimens to the discharge criteria.13
  • In spite of a full resolution of symptoms, stool and sputum samples can remain positive for well over three weeks in some patients.13
  • In a study with rhesus macaques re-challengend with SARS-CoV-2, no recurrence of COVID-19 infection was observed at 5 days post-inoculation, as no viral load was detected in nasopharyngeal and anal swabs and in all target organs.14

At present, short term SARS-CoV-2 reinfection appears to be far less probable than a false-negative nucleic acid test results followed by a subsequent positive test in the context of an incomplete viral clearance, as well as factors such as poor sensitivity of RT-PCR testing, insufficient viral load in throat swab specimens or improper testing technique.15 Long term data is eagerly awaited due to the huge impact of reinfection and immunization in the resolution of the pandemic.

What we know about past coronaviruses and COVID-19 should be analyzed bearing in mind that most of the studies have been done on animal models, that viral and immune responses generally peak earlier in animals than in humans and that the severity of the disease varies among species.16 It’s also important to know that the ELISA method of assessing antibodies’ levels is not as accurate an indicator of immunity as the serum neutralization test17 or as in combination with memory B cells and T cells levels.3

 

This data comes from the analysis of multiple studies.

The 1st study looked at serum antibodies titer in a longitudinal way (6 months, 1, 2 and 3 years) in 176 cases of SARS in Shanxi Province in China. A complete dataset was available for 18 of them. The 2nd study was a two-year prospective unicenter study conducted in Beijing. A cohort of 56 convalescent SARS patients were followed for their IgG and neutralizing antibodies levels. The 3rd study was a six-year longitudinal unicenter study conducted in Beijing that assessed responses to SARS-CoV in 23 recovered patients regarding IgG levels, humoral memory (B cells) and IFN-g memory as a surrogate marker for T cell response. The 4th study was a review on the knowledge base about immunity. The 5th study characterized the neutralizing antibody titer, viral replication, clinical symptoms and lung histopathology after infection of 18 ferrets by intranasal inoculation, with a rechallenge 30 days after primary infection with SARS. The 6th study measured the neutralizing antibody titer and virus titer (RT-PCR) in 10 mice 28 days after primary infection with SARS. Mice were infected by intranasal inoculation. The 7th is a prospective study that measured the neutralizing antibodies titers in 7 patients from Jordan at 13 and 34 month after the primary infection. In the 8th study, the investigators intranasally inoculated MERS-CoV in six rabbits and reinfected them 8 weeks later. The outcomes were viral RNA, viral antigen and perivascular inflammation in lungs. The 9th study was an observational five-month longitudinal study in 2 herds of dromedary camels. Approximately 100 camels have been sampled. Nasal and rectal swabs, as well as serum samples were collected at the beginning of the study and throughout the study. The 10th study was conducted at the Hospital of Jinan University and at Dongguan Ninth People’s Hospital in China, enrolling with seven hospitalized COVID-19 patients from January 30 to February 5, 2020. SARS-CoV-2 infection was confirmed by 2 positive RT-PCR results from throat or rectal swabs. The criteria for discharge 1) no fever for more than three days 2) Significantly decreased respiratory symptoms 3) significantly improved exudative lesions on chest CT and 4) two repetitive RT-PCR test results with at least one day of interval between them. After their discharge, patients were quarantined for at least 2 weeks in designated hospitals and multiple RT-PCR tests were done to assert follow-up. The 11th study was conducted at the Department of Pathology of the Salisbury Infirmary in Salisbury in the UK. Fifteen volunteers were inoculated with coronavirus 229E, and concentrations of circulating and local antibodies were assessed for up to a year after primary infection. Volunteers were then rechallenged with the homologous virus, and symptoms, viral shedding and antibodies concentrations were examined. The 12th study is a case-series conducted with a 58 year-old woman from Wuhan, China, with a COVID-19 infection confirmed with RT-PCR and a positive chest CT scan. Multiple subsequent nucleic acid tests were done to assert follow-up. The 13th study was done in Munich, Germany, and provided a detailed virological analysis of the oro- or nasopharyngeal swab specimens of 9 hospitalized cases. The 14th study was done with four adult Chinese rhesus macaques who were challenged intratracheally with SARS-CoV-2, and body temperatures, X-rays, samples of sera, nasal/throat/anal swabs and samples of primary tissues were carried out.

Sources:

  1. Wu, L. P., Wang, N. C., Chang, Y. H., et al (October 2007). Duration of antibody responses after severe acute respiratory syndrome. Emerging Infectious Diseases. https://doi.org/10.3201/eid1310.070576
  2. Liu, W., Fontanet, A., Zhang, P. H., et al (March 15, 2006). Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. The Journal of Infectious Diseases. https://doi.org/10.1086/500469
  3. Tang, F., Quan, Y., Xin, Z. T., et al (June 15, 2011). Lack of peripheral memory B cell responses in recovered patients with severe acute respiratory syndrome: a six-year follow-up study. The Journal of Immunology. https://doi.org/10.4049/jimmunol.0903490
  4. Ahmed, R., & Gray, D. (April 5, 1996). Immunological memory and protective immunity: understanding their relation. Science. https://doi.org/10.1126/science.272.5258.54
  5. Cameron, M. J., Kelvin, A. A., Leon, A. J., et al (September 24, 2012). Lack of innate interferon responses during SARS coronavirus infection in a vaccination and reinfection ferret model. PLoS One. https://doi.org/10.1371/journal.pone.0045842
  6. Subbarao, K., McAuliffe, J., Vogel, L., et al (March 11, 2004). Prior infection and passive transfer of neutralizing antibodies prevent replication of severe acute respiratory syndrome coronavirus in the respiratory tract of mice. Journal of Virology. https://doi.org/10.1128/jvi.78.7.3572-3577.2004
  7. Payne Dc, Iblan, I., Rha B., et al (October 2016). Persistence of Antibodies against Middle East Respiratory Syndrome Coronavirus. Emerg Infect Dis. https://doi.org/10.3201/eid2210.160706
  8. Houser, K. V., Broadbent, A. J., Gretebeck, L., et al (August 17, 2017). Enhanced inflammation in New Zealand white rabbits when MERS-CoV reinfection occurs in the absence of neutralizing antibody. PLoS Pathogens. https://doi.org/10.1371/journal.ppat.1006565
  9. Hemida, M. G., Alnaeem, A., Chu, D. K., et al (April 17, 2017). Longitudinal study of Middle East Respiratory Syndrome coronavirus infection in dromedary camel herds in Saudi Arabia, 2014-2015. Emerging Microbes & Infections. https://doi.org/10.1038/emi.2017.44
  10. Callow, K. A., Parry, H. F., Sergeant, M., et al (October 1990). The time course of the immune response to experimental coronavirus infection of man. Epidemiology and infection. https://doi.org/10.1017/s0950268800048019
  11. Zhang, B., Liu, S., Dong, Y., et al (April 16, 2020). Positive rectal swabs in young patients recovered from coronavirus disease 2019 (COVID-19), Journal of Infection. https://doi.org/10.1016/j.jinf.2020.04.023
  12. Luo A,. (April 7, 2020). Positive SARS-Cov-2 test in a woman with COVID-19 at 22 days after hospital discharge: A case report. Journal of Traditional Chinese Medical Sciences. https://doi.org/10.1016/j.jtcms.2020.04.001
  13. Wölfel, R., Corman, V. M., Guggemos, W., et al (April 1, 2020). Virological assessment of hospitalized patients with COVID-19. Nature. https://doi.org/10.1038/s41586-020-2196-x
  14. Bao, L., Deng, W., Gao, H., et al (March 14, 2020). Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. bioRxiv. https://doi.org/10.1101/2020.03.13.990226
  15. Marty, F.M., Chen, K., Verrill, K.A. (April 17, 2020). How to Obtain a Nasopharyngeal Swab Specimen. New Eng J Med. https://doi.org/10.1056/NEJMvcm2010260
  16. Resnick, B., & Irfan, U. (2020). What immunity to Covid-19 might actually mean. The Vox guide to navigating the coronavirus crisis, (Apr 27th 2020). https://www.vox.com/science-and-health/2020/4/23/21219028/covid-19-immunity-testing-reinfection-antibodies-explained?fbclid=IwAR0il89q6QMlCAva91AUhWVm5lBV4Dj1YjbOfeBqL8g5glXTmvL7LFNTvng
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