Name: Huzaifa Khan

Student no.: 16195168

Date:01/05/2020

Briefing document on the effect of SARS-CoV-2 on the human immune system

as well as considerations for development of a vaccine

Background

Coronaviruses are defined as non-segmented, enveloped positive-sense RNA viruses that are part of the
family known as Coronaviridae(1). The genomic RNA lying between open reading frame (ORF)1a and
ORF1b, encodes for polyprotein 1a/1ab. Pp1a/pp1ab are responsible for encoding non-structural proteins.
There are 4 main structural proteins encoded by ORFs closest to the 3’ end of the viral genome, known as
spike, membrane, envelope and nucleocapsid proteins (S,M, E and N respectively).

These viruses are able to affect some mammals as well as humans(2). Coronaviruses were first identified
in the 1960’s and were classified into 4 subfamilies. α-coronavirus and β-coronavirus tend to primarily affect
mammals, while γ-coronavirus and δ-coronavirus seem to mainly affect birds(3). The α and β-
coronaviruses typically cause mild infections of the respiratory tract, some are capable of causing
potentially lethal infections of the lower respiratory tract(4).

Of all of the coronaviruses that have the ability to infect humans, only 3 have resulted in pandemics on a
global scale. All 3 were part of the β-subfamily of coronavirus and were of zoonotic origin. The severe acute
respiratory syndrome coronavirus (SARS-CoV) was the first of the coronaviruses to cause deadly
respiratory infections within humans, between 2002 and 2003, displaying a mortality rate of around 10%
(WHO). In 2012, a β-coronavirus was once again the cause of a global pandemic, in the form of the Middle
East Respiratory Syndrome (MERS-CoV) with a mortality rate of 37% (5).

The most recent pandemic caused by a β-coronavirus, beginning in December 2019, was started by a
coronavirus that the World Health Organisation named SARS-CoV-2, causing the severe lower respiratory
tract infection known as Coronavirus Disease 2019 (COVID-19).

Analysis

1. Innate immune response: The innate immune system contains cells that are able to detect and identify
pathogens of a viral nature, by means of pattern recognition receptors, or PRRs. This is done by means of
engagement with pathogen-associated molecular patterns, known as PAMPs(6). PRRs can either be found
within discrete intracellular compartments, or on the surface of the cell. Some examples of PRRs include
Toll-like receptors or TLRs, and nucleic acid sensors.

PRRs function by recognizing unique characteristics of viral RNA that are not typically found on the RNA of
humans, resulting in the activation of innate immune response. This can be done in a few ways, including
detection of the virus extracellularly, by means of TLRs, that are extremely sensitive to proteins and lipids
that are hydrophobic in nature. Another way that viruses trigger the immune response is by means of
recognition of nucleic acids inside the endosome, due to nucleic acid sensors that are able to recognise
that the nucleic materials that is released after the virus coat disintegrates (6).

Based on current, ongoing studies, it has been noted that, like SARS, SARS-CoV-2 seems to enter the
body via Angiotensin converting enzyme 2 (ACE 2) receptors, which are mainly expressed by alveolar Type
2 cells in the lungs (7). Upon entry of the virus into the body, recognition by the immune system is crucial in
order to be able to react to and control the infection.

With regards to coronavirus specifically, the PAMPs are present in the form of single or double-stranded
RNA, of the actively replicating virus. These are easily recognized by the endosomal TLRs, specifically
TLR7 and TLR8, as well as the retinoid inducible gene, a ribonucleic acid sensor known as RIG (6). Once
the PAMPS on the virus are recognized, transcription factors including activator protein 1 (AP1), nuclear
factor κβ (NF-κβ) as well as interferon response factors 3 and 7 (IRF 3 and IRF7) are activated and move
into the nucleus (8). AP1 and NF-κβ stimulate gene expression for genes encoding inflammatory response
molecules including tumour necrosis factor (TNF) and interleukin-1 (IL1) which are inflammatory cytokines,
as well as CCL2 and CXCL8, which are chemokines (8).

Interferon response factors 3 and 7 are responsible for promoting the production of interferon-α and
interferon-β (IFN-α and -β) which have the ability not only to slow down the replication of the virus, but the
spread of the virus within the body as well (9). However, upon infection of a patient by SARS-CoV-2, there
is suppression of the response of type I interferons, IFN-alpha and beta.

It is thus believed, based on supporting evidence from SARS and MERS cases that the suppression or
delay in Type I IFN, compromises early control of the virus, resulting in increased levels of
hyperinflammatory neutrophils and monocytic macrophages, resulting in the induction of pneumonitis,
respiratory distress as well as potential lung damage(8).

Upon analysis of existing literature and data on infections by coronaviruses, it seems that viruses actively
replicating cause an extremely increased production of IFN Type I as well as macrophage and neutrophil
influx. These are 2 major sources of pro-inflammatory cytokines(10).

When looking at the lymphocyte and neutrophil levels of patients with SARS-CoV-2, it was noted that there
was an increase in total neutrophils and a decrease in total lymphocytes, resembling levels similar to those
found within patients with SARS. Therefore, it is likely that in case of SARS-CoV-2 infection, there is a
delay in Type 1 IFN in addition to a loss of control of the virus, during the earlier phases of infection(10).

The fact that individuals that are immunocompromised and at a high risk of dying from SARS-CoV-2
infection are individuals with underlying conditions such as cardiovascular disease and diabetes, while
young children seem to be at lowest risk, indicated a strong relationship between the innate immune
response and mortality. This can be tied to already elevated levels of proinflammatory cytokines and
decreased Type I IFN, in immunocompromised individuals, indicating that innate immune response
targeting therapies may be effective at controlling infection(10).

2. Adaptive immune response:

Adaptive immunity can be defined as the immunity that can be transferred between organisms by means of
lymphoid cells rather than serum antibodies. This kind of immune response is typically mediated by Primary
T-cells, NK cells as well as macrophages. T-cells can be broken into 2 types, which are CD4+ T-cells that
stimulate other immune cells, and CD8+ T-cells which are cytotoxic response cells that kill cells that are
infected(11).

When a virus infects a person, it hijacks the protein-synthesis systems within host cells, to make viral
proteins. While this occurs, some of the viral proteins will be broken down into fragments, some of which
possess adequate affinity to bind to MHC-I (Major Histocompatability Complex, Class I) molecules. This
new MHC I-protein fragment complex will present itself on the surface of the infected cell, which acts as a
marker for the CD8+ T-cell(11).

The CD8+ T-cell needs to be activated in order to be able to induce apoptosis of the infected cell. This
happens in lymph nodes, when antigen-presenting cells (e.g. Dendritic cells), known as APCs, encounter
naïve T-cells. The interaction between the CD4+ cells and dentritic cells provide the stimulatory effect that
is necessary to activate the CD8+ cells(11). Once active, CD8+ T-cells that are specific for the protein
fragment being presented on the infected cell, will recognise the complex and release cytotoxic granules
inducing apoptosis of the infected cell.

CD4+ T-cells can be split into different classes, depending on the cytokines and chemokines they produce.
These classes are Th1, Th2 and Tregs. Th1 cells produce IFN-γ while Th2 cells produce Interleukins 4,5
and 13(11).

In cases of viral infections, the adaptive immunity of the patient is typically dominated by Th1-type immune
response. This is because Th1 responses are generally efficient at viral control. However, viruses are able
to overcome this response system by means of downregulation of interferon production(12). T-cell
responses to SARS was investigated, showing between response of T-cells, neutralisation of the virus and
the incidence of different cytokines in different risk groups. A strong response of T-cells seemed to show a
significant correlation to higher neutralizing ability, while in the extreme-risk group, there were significant
elevations of Th2 cytokines like interleukins 4,5 and 10 (6).

Due to the fact that SARS and MERS infections were brought under control by the Th1 class and that
SARS-CoV-2 is genomically 79% similar to SARS, it is very likely that an effective Th1 response holds the
key to successful treatment of COVID-19.

3. Yes it would. Based on vaccine research done previously, in response to the SARS and MERS outbreak,
it is safe to assume that there is sufficient information with regards to the best approach to vaccine
development. While conducting research on SARS and MERS, it was found that nucleic acid-based
vaccines showed the most promise. Some potential avenues for vaccine creation include(13):
DNA vaccines can be designed easily (using the viral D/RNA) and induce adaptive response. However, it
may not have as strong an effect as a live virus.

Subunit vaccines can be created around the viral protein subunits as subunit vaccines are safe and
effective. However, it may be very costly.

Inactivated vaccines can be made using an inactive form of the viral agent can be developed quickly and
co-formulated with adjuvants. However, they can cause hypersensitivity/allergic reactions(11).

Attenuated-live vaccines can be made using an attenuated form of the virus as it stimulates B-cell and T-
cell responses very well. However, it would not be able to be administered to risk-groups including children,
elderly and immunocompromised patients.

4. Vaccines work by simulating an infection in the patient, in order to allow the patient to develop immunity
to the pathogen responsible(14). This kind of infection does not usually result in sickness as it most often is
made of an inactive or attenuated form of the microorganism in question. Upon introduction of the vaccine
into the body, the immune system produces T-lymphocytes as well as antibodies, in response to the
simulated infection. After some minor symptoms like a fever recedes, the T-cells differentiate into memory
T-cells as well as B-cells that are able to instantly recognize the pathogen in the future and react rapidly
enough to get the infection under control without causing illness(14).

Minor symptoms may be seen just after administration of vaccines as a result of the immunological
response of the body to the vaccine, but generally subside after a few days, as the immune response
subsides. However , in the case of an infection by the pathogen vaccinated against, a secondary
immunological response is stimulated, as the memory cells recognize the pathogen, and this occurs in a
strong and rapid manner, thus causing a rapid elevation of immune activity and a rapid depression of the
immune activity after the infection has been contained. This can be visualised using an antibody-response
graph:

Antibody-response graph
Antibody Levels

Response

0 2 4 6 8 10 12
Time
1. Vaccine introduced

2. Primary response- slight elevation of

antibodies temporarily

3. Memory cells remaining after vaccine

1
3
administration

4.Rapid secondary immune response4 after

2
infection by pathogen vaccinated against.
5. Immunocompromised individuals are those individuals who have an immune system that is functioning
below optimum levels. Typically, these are primarily cancer patients undergoing chemotherapy or patients
suffering from HIV/AIDS. These individuals tend to experience some form of immunosuppression as a
result of the infection/drugs(15).

Mildly immunosuppressed patients typically include asymptomatic HIV+ patients with a CD4+ count of
between 15 and 24%, as well as cancer patients that are on low-dose methotrexate (less than 0.4
mg/kg/week) or mercaptopurine (less than 1.5 mg/kg/week). Severely immunosuppressed patients include
cancer patients on aggressive chemo- and radiotherapy regimens, people who have undergone organ
transplantation within 2 months and HIV+ individuals with a CD4+ count of less than 15%(15).

Thus, vaccination administration to immunocompromised patients is dependant on level of

immunosuppression as well as the type of vaccination being used. The following are guidelines for different
vaccine forms(15):

Live vaccines should not be administered to severely immunocompromised patients or patients who have
unknown immune response but may be administered to mildly immunosuppressed patients if benefits
outweigh the side-effects.

All inactive vaccines can be administered as necessary to patients with primary immune deficiency (lack of
cellular and/or humoral immunity) or secondary immune deficiency (developed loss of cellular and/or
humoral immunity as a result of disease or drugs).
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