The proposed study is designed to investigate if and how pregnant women infected withCoronavirus Disease-19 (COVID-19) infection go on to develop long-term immunity. InDecember 2019, a group of people in Wuhan, China presented with symptoms of a pneumoniaof 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 deathsas of 13th June 2020. In the United Kingdom (UK), there have been 294,000 cases and41,662 deaths as of 13th June 2020. In humans, this infection primarily involves theupper part of the lungs, but it can also affect other organs. It causes mild symptoms inthe majority of people affected but some people can have severe infections, with someeven requiring critical care in hospital. During Severe acute respiratory syndrome(SARS), a previous coronavirus epidemic, pregnant women were disproportionately affectedwith severe illness. Understanding how the immune system responds long-term to thisinfection 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 maynot behave effectively. This may affect their ability to develop long lasting immunityand make them more vulnerable to re-infection. In this study, the investigators aim torecruit patients across 6 groups including COVID-19 newly infected pregnant women, andpeople with differing illness severity, mild to moderate, severe/critical, no infection(controls), as well as pregnant women with influenza and those receiving influenzavaccine. The study team will compare COVID-19 in pregnancy with non-pregnant infected andwith influenza infected and vaccinated pregnant women. The study team will consentpatients in all of these groups to provide a series of blood samples at different timepoints in a 12-month period.
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.
Procedure: Blood sample
Peripheral blood sample will be obtained.
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
Chelsea and Westminster NHS Foundation Trust
London, United Kingdom
Imperial College Healthcare NHS Trust
London, United Kingdom
Nishel M Shah, PhD, Principal Investigator
Imperial College London