The adaptive immune response to COVID-19 infection ASHM COVID-19 Taskforce interim report

The first report of the immune response to SARS-CoV-2 was from Melbourne, Australia and showed that both B cell and T cell responses occurred during the clinical illness of a woman hospitalised with COVID-19 illness(4). Further reports have since emerged from China providing more details on the timing and development of IgM and IgG antibody responses in patients hospitalised with SARS-CoV-2 infection(4-6) and are summarised in Table 1.

 

Table 1. Adaptive immune responses to SARS-CoV-2 infection

Study	Patients N=Number Confirmed = SARS-CoV-2 RNA PCR positive	Total Ab and IgM Ab	IgG Ab	B and T cell responses
Thevarajan et al, Nat Med, 2020	N= 1 Hospitalised Confirmed	IgM detected on day 7	IgG detected on day 7	Antibody secreting cells, circulating follicular helper T cells and CD38+HLA-DR+ CD8+ T cells detected on day 7
Zhao et al, Clin Infect Dis 2020	N= 173 All hospitalised All confirmed	Median time to total Ab seroconversion: 11 days   Total Ab present Week 1: 36/94 samples Week 2: 121/135 samples Week 3: 90/90 samples   Median time to IgM Ab seroconversion: 12 days   IgM Ab present Week 1: 27/94 samples Week 2: 99/135 samples Week 3: 83/90 samples	Median time to IgG Ab seroconversion: 14 days           IgG Ab present Week 1: 18/94 samples Week 2: 73/135 samples Week 3: 71/90 samples	N/A
Guo et al Clin Infect Dis, 2020	N= 140 All hospitalised N= 82 confirmed N= 58 probable	Median time to IgM Ab detection, 5 days [IQR 3-6]   35/41 (85.4% ) samples tested at week 1 were positive for IgM Ab	Median time to IgG Ab detection, 14 days [IQR 10-18]   162/208 (77.9%) samples were positive for IgG Ab	N/A

 

A recent paper which has not yet been peer reviewed, has provided data on the neutralising antibodies produced during SARS-CoV-2 infection(7). The authors reported on 175 patients hospitalised with confirmed mild COVID-19 illness; all patients recovered. In the 175 patients, SARS-CoV-2 specific neutralising antibodies were detected at days 10-15 following illness onset. Of note, 30% of these patients generated low titres of SARS-CoV-2 specific neutralising antibodies, despite their full recovery. Also of note, older patients developed higher levels of SARS-CoV-2 specific neutralising antibodies and the titres of these patients’ antibodies were significantly higher than those of younger patients(7). Further data are needed on SARS-CoV-2 specific neutralising antibodies to determine their role in future protection against COVID-19 illness and to guide vaccine development.

There are several key issues arising in these early studies on the adaptive immune response to SARS-CoV-2. Importantly, antibodies targeted the receptor binding domain of the SARS-CoV-2 spike protein and the SARS-CoV-2 specific neutralising antibodies reflect immune responses that are likely to protect against SARS-CoV-2 infection. However, the immune protective effect of antibodies which target other viral elements, such as the IgG antibodies that were reported in Zhao et al, which bind to the viral nucleoprotein(5), are not known. Other key issues include that the timing of the sampling of antibody responses varies between studies, making it hard to confidently determine the time to seroconversion following infection with SARS-CoV-2; there is likely to be variability in the reporting of symptom onset in patients; the follow-up periods are short in these studies hence the longevity and the levels of IgM and IgG antibodies are not yet well described and finally the studies remain relatively small at this stage.

The durability of the immune response and the relative contribution of B and T cell responses to SARS-CoV-2 infection have not yet been ascertained. It is plausible that longterm immunity to SARS-CoV-2 may be conferred largely by T cells. Of 23 patients infected with the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), 60% had virus specific memory T cell responses six years following their acute infection with SARS-CoV (8). By contrast specific IgG antibody to SARS-CoV was not detected in any of these patients.

Less is known about the long-term immune protection against Middle Eastern Respiratory Syndrome coronavirus (MERS- CoV) infection. In mice, both antibody and T cell responses are important for initial clearance of the virus(9). In one small study, six of seven humans with prior probable MERs-CoV infection were shown to have neutralising antibodies detected 34 months following the original outbreak in Jordan(10). However whether these neutralising antibodies are protective against re-infection with MERs-CoV is unknown.

There are currently very few data available to determine how long lasting the immune response is following infection with SARS-CoV-2 and whether it confers protection against re-infection.

Recently a small study reported results from the rechallenge of three rhesus macaques with SARS-CoV-2 and found that re-infection did not occur following re-challenge with the virus (11).  Results from this study should be interpreted carefully because it has not yet been peer reviewed, the study was relatively small and the monkeys were re-challenged 28 days after their initial infection so one cannot deduce that longterm immunity was conferred.

In this study four rhesus macaques were infected intra-tracheally with SARS-CoV-2 and all developed signs of illness wherein the monkeys remained afebrile but had weight loss, increased respiratory rate and pneumonia occurred in at least two monkeys. SARS-CoV-2 viral loads from nasal, pharyngeal and anal swabs peaked at day 3. One monkey was sacrificed at day 7 and the virus was detected in numerous tissues including the lung where features of pneumonia were present. Prior to intra-nasal re-challenge at day 28, the authors reported that the remaining three monkeys were clinically stable with clear chest x-rays and negative nasopharyngeal and anal swabs. Two monkeys were rechallenged intra-tracheally and the authors reported that both had a rise in temperature, but no weight loss. One monkey was sacrificed at day 5 post re-challenge and no virus was detected in any tissues and no pathological changes were observed it the lung. Repeat nasaopharyngeal and anal swabs remained negative post-rechallenge in the remaining monkey over several days(11).

Broadly, the current thinking among virologists and immunologists is that the immune response is likely to be protective against re-infection with SARS-CoV-2 , but more data are required to determine this.

It is estimated that between 18%-30% of people with SARS-CoV-2 infection remain asymptomatic, i.e. do not develop symptoms despite being infected with the virus(12-15). There are currently no data on the nature of the adaptive immune response in people with asymptomatic SARS-CoV-2 infection.

There are currently no data available to determine whether these populations are less likely to develop an effective adaptive immune response to SARS-CoV-2. More data are required in these patient populations.

1. National COVID-19 Clinical Evidence Taskforce https://covid19evidence.net.au/.

2. New York Times https://www.nytimes.com/2020/04/11/us/coronavirus-survivors.html?searchResultPosition=1.

3. New York times. https://www.nytimes.com/2020/04/04/world/europe/italy-coronavirus-antibodies.html.

4. Thevarajan, I., T. H. O. Nguyen, M. Koutsakos, J. Druce, L. Caley, C. E. van de Sandt, X. Jia, S. Nicholson, M. Catton, B. Cowie, S. Y. C. Tong, S. R. Lewin, and K. Kedzierska. 2020. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19. In Nature Medicine.

5. Zhao, J., Q. Yuan, H. Wang, W. Liu, X. Liao, Y. Su, X. Wang, J. Yuan, T. Li, J. Li, S. Qian, C. Hong, F. Wang, Y. Liu, Z. Wang, Q. He, Z. Li, B. He, T. Zhang, Y. Fu, S. Ge, L. Liu, J. Zhang, N. Xia, and Z. Zhang. 2020. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis.

6. Guo, L., L. Ren, S. Yang, M. Xiao, Chang, F. Yang, C. S. Dela Cruz, Y. Wang, C. Wu, Y. Xiao, L. Zhang, L. Han, S. Dang, Y. Xu, Q. Yang, S. Xu, H. Zhu, Y. Xu, Q. Jin, L. Sharma, L. Wang, and J. Wang. 2020. Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19). Clin Infect Dis.

7. Fan Wu, Aojie Wang, Mei Liu, Qimin Wang, Jun Chen, Shuai Xia, Yun Ling, Yuling Zhang, Jingna Xun, Lu Lu, Shibo Jiang, Hongzhou Lu, Yumei Wen, Jinghe Huang. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. https://www.medrxiv.org/content/10.1101/2020.03.30.20047365v1.full.pdf.

8. Tang, F., Y. Quan, Z. T. Xin, J. Wrammert, M. J. Ma, H. Lv, T. B. Wang, H. Yang, J. H. Richardus, W. Liu, and W. C. Cao. 2011. Lack of peripheral memory B cell responses in recovered patients with severe acute respiratory syndrome: a six-year follow-up study. J Immunol 186: 7264-7268.

9. Mubarak, A., W. Alturaiki, and M. G. Hemida. 2019. Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Infection, Immunological Response, and Vaccine Development. J Immunol Res 2019: 6491738.

10. Payne, D. C., I. Iblan, B. Rha, S. Alqasrawi, A. Haddadin, M. Al Nsour, T. Alsanouri, S. S. Ali, J. Harcourt, C. Miao, A. Tamin, S. I. Gerber, L. M. Haynes, and M. M. Al Abdallat. 2016. Persistence of Antibodies against Middle East Respiratory Syndrome Coronavirus. Emerg Infect Dis 22: 1824-1826.

11. Linlin Bao L, Wei Deng, Hong Gao, Chong Xiao,, Jiayi Liu, Jing Xue, Qi Lv, Jiangning Liu, Pin Yu, Yanfeng Xu, Feifei Qi, Yajin Qu, Fengdi Li, Zhiguang Xiang, Haisheng Yu, Shuran Gong, Mingya Liu, Guanpeng Wang, Shunyi Wang, Zhiqi Song, Wenjie Zhao, Yunlin Han, Linna Zhao, Xing Liu, Qiang Wei, Chuan Qin. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. https://www.biorxiv.org/content/10.1101/2020.03.13.990226v1.full.pdf.

12. Mizumoto, K., K. Kagaya, A. Zarebski, and G. Chowell. 2020. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill 25.

13. Pan, X., D. Chen, Y. Xia, X. Wu, T. Li, X. Ou, L. Zhou, and J. Liu. 2020. Asymptomatic cases in a family cluster with SARS-CoV-2 infection. Lancet Infect Dis 20: 410-411.

14. Chan, J. F., S. Yuan, K. H. Kok, K. K. To, H. Chu, J. Yang, F. Xing, J. Liu, C. C. Yip, R. W. Poon, H. W. Tsoi, S. K. Lo, K. H. Chan, V. K. Poon, W. M. Chan, J. D. Ip, J. P. Cai, V. C. Cheng, H. Chen, C. K. Hui, and K. Y. Yuen. 2020. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 395: 514-523.

15. Nishiura, H., T. Kobayashi, A. Suzuki, S. M. Jung, K. Hayashi, R. Kinoshita, Y. Yang, B. Yuan, A. R. Akhmetzhanov, N. M. Linton, and T. Miyama. 2020. Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19). Int J Infect Dis.