Evaluation of Humoral Immunity Following COVID-19 in Pregnancy

COVID-19 Clinical Trial

— ImmunoCOVID  

Official title:

Evaluation of Cell-mediated and Humoral Immunity Following COVID-19 in Pregnancy

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04568044
• Other study ID #: 20SM6089
• Status: Active, not recruiting
• Start date: September 16, 2020
• Est. completion date: January 1, 2025

Study information

• Verified date: February 2024
• Source: Imperial College London
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The proposed study is designed to investigate if and how pregnant women infected with Coronavirus Disease-19 (COVID-19) infection go on to develop long-term immunity. In December 2019, a group of people in Wuhan, China presented with symptoms of a pneumonia of an unknown cause that led to the discovery of a new coronavirus called COVID-19. COVID-19 has caused a global pandemic with 7,140,000 confirmed cases and 418,000 deaths as of 13th June 2020. In the United Kingdom (UK), there have been 294,000 cases and 41,662 deaths as of 13th June 2020. In humans, this infection primarily involves the upper part of the lungs, but it can also affect other organs. It causes mild symptoms in the majority of people affected but some people can have severe infections, with some even requiring critical care in hospital. During Severe acute respiratory syndrome (SARS), a previous coronavirus epidemic, pregnant women were disproportionately affected with severe illness. Understanding how the immune system responds long-term to this infection may hold the key to developing better vaccines and efficient treatment plans. Specialised immunity develops when individuals are infected by this and other viruses. The investigators of this study propose that, in pregnancy, this specialised immunity may not behave effectively. This may affect their ability to develop long lasting immunity and make them more vulnerable to re-infection. In this study, the investigators aim to recruit patients across 6 groups including COVID-19 newly infected pregnant women, and people with differing illness severity, mild to moderate, severe/critical, no infection (controls), as well as pregnant women with influenza and those receiving influenza vaccine. The study team will compare COVID-19 in pregnancy with non-pregnant infected and with influenza infected and vaccinated pregnant women. The study team will consent patients in all of these groups to provide a series of blood samples at different time points in a 12-month period.

Description:

Background

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), commonly known as Coronavirus Disease-19 (COVID-19), is a global pandemic with 7,410,000 confirmed cases and 418,000 deaths as of 13th June 2020. It is believed that SARS-CoV-2 shares 79.6% of its sequence identity with SARS-CoV and resembles some clinical outcomes like viral pneumonia. However, it causes milder symptoms in majority of people infected, and can be an asymptomatic infection in some individuals. Just in the 21st century, we have seen three major coronavirus (CoV) outbreaks: SARS-CoV, Middle East respiratory syndrome (MERS)-CoV, and the novel SARS-CoV-2, which have resulted in many deaths and have posed a real threat to public health. In fact, during SARS more pregnant women required intensive care and ventilation, and the number of deaths was higher when compared to non-pregnant adults. This is partly because in pregnancy, the risk of viral pneumonia is greater compared to the general population.

Understanding T and B cell mediated immunity in COVID-19 participants may hold the key to developing better vaccines and efficient treatment plans. To date there is only one study that has investigated circulatory T follicular helper cells (cTFH), which like there germinal centre counterparts are a specialised effector cluster of differentiation 4 (CD4) T cell that induces B cell activation, and differentiation into class-switched and antibody secreting long-lasting plasmablasts. This study observed an increase in cTFH during pregnancy. However, studies in older patients, which comprise another high risk group, have shown mixed results with cTFH showing lower levels of activation. This will impact on long term antibody production following infection or vaccination. We propose that circulatory cTFH, and B cells may not be as activated in both pregnant women and patients with severe to critical patients when compared with mild to moderate patients resulting in less or poorly functioning anti-SARS-CoV-2 antibodies. Therefore, we expect in infected pregnant individuals the development of long-term immunity may be worse when compared to non-pregnant people with similar disease severity, making them more susceptible to re-infection. Compared to influenza, which is another respiratory illness with significant morbidity in pregnancy and has a current vaccination program, we expect that the same measures of immunity will be less pronounced post COVID-19 infection. Furthermore, the development of long-term immunity will be less effective in patients with severe illness, who for the most part, comprise a particularly high-risk group including the elderly and patients with multiple comorbidities. It is vital that we expand our knowledge of long-lasting immunity in individuals who have recovered from COVID-19 to see how long these individuals are protected against re-infection and whether they develop long lasting immunity. Moreover, there is no current research establishing the parameters of seroprotective immunity. Previous research has suggested that SARS-CoV specific Immunoglobin G (IgG) declines significantly within 2 years with some reports showing a complete loss within 6 years in most SARS-CoV recovered patients. This may equate to a loss of long-term protection. The investigators of this study propose measuring SARS-CoV-2 specific IgG levels by doing memory B cell (Enzyme-Linked ImmunoSpot) ELISpots and comparing the data with cTFH and B cell flow cytometry panels. The research team will be able to profile the generation and persistence of protective antibodies produced by infected individuals who go on to recover. The findings from this study will generate hypotheses to be tested in larger studies of COVID-19 recovered pregnant patients, and also assist researchers working trying to understand the effectiveness of the vaccines in pregnancy once these become commercially available.

Research Question

In pregnant individuals who have recovered from COVID-19:

A. How long will their SARS-CoV-2 specific Immunoglobulin G (IgG) levels remain in peripheral blood, what is the rate of decline and how does this compare to non-pregnant individuals?

B. How did their T cell mediated immune function differ from non-pregnant patients during the infection?

C. How do their SARS-CoV-2 specific memory T cell differ when compared to severe to non-pregnant patients' post-recovery?

D. How does antibody production, and B and T cell function post COVID-19 infection in pregnancy compare with influenza infection and vaccination?

Hypothesis

The investigators hypothesise that pregnant patients with COVID-19 will develop a less robust and measurable B-cell response when compared to influenza infected/vaccinated women and non-pregnant individuals, and that their seroprotective antibody responses will decline by 12 months post infection.

Study Aims

A. Establish robust assays to measure SARS-CoV-2-specific IgG from individuals who have recovered from COVID-19 infection and track these levels over a 12-month period to measure any decline. In pregnancy, compare this to influenza antibodies produced after infection and vaccination.

B. Measure frequency of activated cTFH, and antigen-secreting cells (ASCs) at days 7-14 of symptom onset in pregnant patients with COVID-19 and compare with non-pregnant groups, and pregnant influenza infected and influenza vaccinated. In addition, compare between non-pregnant groups with mild to moderate symptoms when compared to severe to critical patients.

C. Measure frequency of activated memory B cells at day 28 in pregnant patients with COVID-19 and compare with non-pregnant groups, and pregnant influenza infected and influenza vaccinated. In addition, compare between non-pregnant groups with mild to moderate symptoms when compared to severe to critical patients.

D. Measure frequency of CD4 and cluster of differentiation 8 (CD8) T cells in pregnant patients with COVID-19 and compare with non-pregnant groups, and pregnant influenza infected and influenza vaccinated. In addition, compare between non-pregnant groups with mild to moderate symptoms when compared to severe to critical patients.

E. Quantify antigen-specific memory T cells and measure frequency of activated T cells in all patient groups.

F. Quantification of SARS-CoV-2 viral load from infected participants.

Study Design

This study will be a prospective observational project to investigate the potential decline of protective immunity in pregnancy after participants have recovered from SARS-CoV-2. The research team will compare these findings with non-pregnant patients who have had COVID-19 and developed mild to moderate symptoms or severe to critical participants. Patients who go on to join a SARS-CoV-2 vaccine trial will not be excluded but the vaccination date will be recorded, and their results interpreted accordingly. In order to compare COVID-19 infection with another respiratory infection and assess long term protective immunity with an intervention already in place in this patient group designed to provide seroprotective antibodies, the investigators will investigate influenza and influenza vaccine. Therefore, data from pregnant patients will also be compared with influenza infected pregnant women and those who have received the influenza vaccination.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 128
• Est. completion date: January 1, 2025
• Est. primary completion date: January 1, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

1. Group A: Mild to moderate COVID-19 (non-pregnant)

• Current male or female COVID-19 infected (age 18-60 years old) with mild to moderate illness

2. Group B: Severe to critical COVID-19 (non-pregnant)

• Current male or female COVID-19 infected (age 18-60 years old) with severe to critical illness

3. Group C: Controls (non-pregnant)

• Male of female uninfected (age 18-60 years old) who have no history of COVID-19 symptoms or illness

4. Group D: Pregnant or postnatal with COVID-19

• Current pregnant or postnatal COVID-19 infected (age 18-50 years old)

• Pregnant or postnatal (within 6 weeks since birth) who were diagnosed with COVID-19 less than 4 months previously (age 18-50 years old)

• Singleton pregnancy

5. Group E: Pregnant or postnatal with influenza

• Current pregnant or postnatal influenza infected (age 18-50 years old)

• Pregnant or postnatal (within 6 weeks since birth) who were diagnosed with influenza less than 4 months previously (age 18-50 years old)

• Singleton pregnancy

6. Group F: Pregnant and have received the influenza vaccine

• Current pregnant who has received the influenza vaccine (age 18-50 years old)

• Singleton pregnancy

Exclusion Criteria:

1. Group A, Group B and Group C:

• Patients unable to understand verbal or written information in English, regarding the study. Lack of capacity to consent at the point of recruitment

• Pregnant

• Participants who have previously been part of any SARS-CoV-2 vaccine trial

• Evidence of HIV infection

• Participants on medication that may significantly affect their immune system such as chemotherapy drugs

• Vulnerable patients with known safe-guarding issues

• Pregnant with more than one baby

2. Group D, E and F:

• Patients unable to understand verbal or written information in English, regarding the study.

• Lack of capacity to consent at the point of recruitment

• Participants who have previously been part of any SARS-CoV-2 vaccine trial

• Evidence of HIV infection

• Participants on medication that may significantly affect their immune system such as chemotherapy drugs other than steroids, which have been given for fetal lung maturity

• Vulnerable patients with known safe-guarding issues

• Pregnant with more than one baby

Related Conditions & MeSH terms

• COVID-19
• Influenza, Human
• Pregnancy Related

Intervention

Procedure:
• Blood sample
Peripheral blood sample will be obtained.

Locations

Country	Name	City	State
United Kingdom	Chelsea and Westminster NHS Foundation Trust	London
United Kingdom	Imperial College Healthcare NHS Trust	London

Sponsors (1)

Lead Sponsor	Collaborator
Imperial College London

Country where clinical trial is conducted

United Kingdom, 

References & Publications (11)

Bentebibel SE, Khurana S, Schmitt N, Kurup P, Mueller C, Obermoser G, Palucka AK, Albrecht RA, Garcia-Sastre A, Golding H, Ueno H. ICOS(+)PD-1(+)CXCR3(+) T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination. Sci Rep. 2016 May 27;6:26494. doi: 10.1038/srep26494. — View Citation

Brenna E, Davydov AN, Ladell K, McLaren JE, Bonaiuti P, Metsger M, Ramsden JD, Gilbert SC, Lambe T, Price DA, Campion SL, Chudakov DM, Borrow P, McMichael AJ. CD4+ T Follicular Helper Cells in Human Tonsils and Blood Are Clonally Convergent but Divergent from Non-Tfh CD4+ Cells. Cell Rep. 2020 Jan 7;30(1):137-152.e5. doi: 10.1016/j.celrep.2019.12.016. — View Citation

Herati RS, Reuter MA, Dolfi DV, Mansfield KD, Aung H, Badwan OZ, Kurupati RK, Kannan S, Ertl H, Schmader KE, Betts MR, Canaday DH, Wherry EJ. Circulating CXCR5+PD-1+ response predicts influenza vaccine antibody responses in young adults but not elderly adults. J Immunol. 2014 Oct 1;193(7):3528-37. doi: 10.4049/jimmunol.1302503. Epub 2014 Aug 29. — View Citation

Kong WH, Li Y, Peng MW, Kong DG, Yang XB, Wang L, Liu MQ. SARS-CoV-2 detection in patients with influenza-like illness. Nat Microbiol. 2020 May;5(5):675-678. doi: 10.1038/s41564-020-0713-1. Epub 2020 Apr 7. — View Citation

Linterman MA. How T follicular helper cells and the germinal centre response change with age. Immunol Cell Biol. 2014 Jan;92(1):72-9. doi: 10.1038/icb.2013.77. Epub 2013 Nov 12. — View Citation

Matsui K, Adelsberger JW, Kemp TJ, Baseler MW, Ledgerwood JE, Pinto LA. Circulating CXCR5(+)CD4(+) T Follicular-Like Helper Cell and Memory B Cell Responses to Human Papillomavirus Vaccines. PLoS One. 2015 Sep 2;10(9):e0137195. doi: 10.1371/journal.pone.0137195. eCollection 2015. — View Citation

Sahu KK, Mishra AK, Lal A. Coronavirus disease-2019: An update on third coronavirus outbreak of 21st century. QJM. 2020 May 1;113(5):384-386. doi: 10.1093/qjmed/hcaa081. No abstract available. — View Citation

Tang F, Quan Y, Xin ZT, Wrammert J, Ma MJ, Lv H, Wang TB, Yang H, Richardus JH, Liu W, Cao WC. Lack of peripheral memory B cell responses in recovered patients with severe acute respiratory syndrome: a six-year follow-up study. J Immunol. 2011 Jun 15;186(12):7264-8. doi: 10.4049/jimmunol.0903490. Epub 2011 May 16. — View Citation

Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. 2012;30:429-57. doi: 10.1146/annurev-immunol-020711-075032. Epub 2012 Jan 3. — View Citation

Wong SF, Chow KM, Leung TN, Ng WF, Ng TK, Shek CC, Ng PC, Lam PW, Ho LC, To WW, Lai ST, Yan WW, Tan PY. Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome. Am J Obstet Gynecol. 2004 Jul;191(1):292-7. doi: 10.1016/j.ajog.2003.11.019. — View Citation

Zhou M, Zou R, Gan H, Liang Z, Li F, Lin T, Luo Y, Cai X, He F, Shen E. The effect of aging on the frequency, phenotype and cytokine production of human blood CD4 + CXCR5 + T follicular helper cells: comparison of aged and young subjects. Immun Ageing. 2014 Aug 23;11:12. doi: 10.1186/1742-4933-11-12. eCollection 2014. Erratum In: Immun Ageing. 2015;12:13. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phenotyping antibody secreting cells (ASCs) and memory B cells during COVID-19 infection, and post recovery.	Devise a flow cytometry panel to phenotype B cells.	Groups A, B, D: Between 4 months with a minimum of 2 time points (i.e. 8 and 12 months), and 12 months with a maximum 5 time points (i.e. 7-14 days, then 1, 4, 8, 12 months) post infection. Group C: 1 day. 1 time point.
Primary	Quantification of SARS-CoV-2 specific IgG production by memory B cells to measure long-lasting immune protection against re-infection.	B cell ELISpot assay and quantify Immunoglobulin A (IgA) and IgG using Enzyme-linked immunosorbent assay (ELISA) from plasma and/or serum from COVID-19 recovered individuals.	Groups A, B, D: Between 4 months with a minimum of 2 time points (i.e. 8 and 12 months), and 12 months with a maximum 5 time points (i.e. 7-14 days, then 1, 4, 8, 12 months) post infection. Group C: 1 day. 1 time point.
Secondary	Quantification of SARS-COV-2 viral load using PCR.	Use real-time PCR (RT-PCR) and nested PCR to detect SARS-CoV-2 viral load	Groups A, B, D: at 7-14 days and during recovery phase. Group C: 1 day. 1 time point.
Secondary	Immuno-phenotype circulatory T follicular helper cells (cTFH) cells post SARS-CoV-2 infection.	Devise a flow cytometry panel to phenotype cTFH cells.	Groups A, B, D: at 7-14 days post infection or vaccination. Group C: 1 day. 1 time point.
Secondary	Investigating T cell mediated immune function post COVID-19	Use a combination of flow cytometry, enzyme-linked immunospot (ELISpot) assays, and DNA/RNA analysis.	Groups A, B, D: Between 4 months with a minimum of 2 time points (i.e. 8 and 12 months), and 12 months with a maximum 5 time points (i.e. 7-14 days, then 1, 4, 8, 12 months) post infection/vaccination. Group C: 1 day. 1 time point.
Secondary	In pregnancy, comparing antibody production, and immune phenotype and function (as outlined above) between COVID-19 infection, and influenza infected or vaccinated.	Parameters including antibody titres, cTFH and memory B cell and ASC proportions, and T cell function will be compared between COVID-19 infected, and influenza infected and vaccinated pregnant women.	Groups A, B, D, E and F: Between 4 months with a minimum of 2 time points (i.e. 8 and 12 months), and 12 months with a maximum 5 time points (i.e. 7-14 days, then 1, 4, 8, 12 months) post infection/vaccination. Group C: 1 day. 1 time point.

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