Can Epstein-Barr virus cause multiple sclerosis?

 

Multiple sclerosis (MS) is an autoimmune condition thought to arise from a combination of environmental and genetic factors. A growing body of evidence has emerged over the last several years suggesting Epstein-Barr virus (EBV), a member of the herpes virus family, is a major environmental risk factor for MS.

What is Epstein-Barr virus?

EBV, or human herpesvirus 4, is one of the most common viruses worldwide. It is transmitted through bodily fluids, especially saliva, but also through blood and semen. Infection with EBV often occurs in childhood, but can affect a person at any life stage.

Almost all people are infected with EBV at some point in their lives — estimates indicate that about 90% of adults worldwide are infected with the virus. However, the infection is usually asymptomatic or with symptoms similar to a mild cold, and most people may never know they have been infected.

EBV is the leading cause of infectious mononucleosis, commonly known as mono, or the “kissing disease.” As such, it may be accompanied by symptoms that include fever, fatigue, sore throat, rash, and an enlarged liver or spleen.

The virus works by infecting B-cells, which are immune cells responsible for producing the antibodies that attack foreign substances, known as antigens. In the human body, EBV has two phases of its life cycle: the lytic cycle, when it is actively reproducing; and the latent cycle, where it lies dormant inside B-cells.

It also is possible for the virus to reactivate after entering the latent phase, which may or may not cause symptoms.

Is EBV associated with MS?

A link between EBV and the development of MS has long been suspected. Several research studies demonstrated that most MS patients have antibodies against the EBV virus — an indicator of a prior infection — and that their antibody levels are higher than those in healthy people exposed to the virus.

Furthermore, the HLA-DRB1*1501 MS genetic risk variant — the strongest genetic risk factor for MS — also has been associated with increased antibody levels against components of EBV. Accumulating research has also linked prior illness with mono to an increased risk of developing MS.

Despite the abundance of earlier research, a causal link between EBV and MS had been difficult to establish.

Two studies published early in 2022 — one from Harvard University and one from Stanford University — have significantly propelled the understanding of this relationship and provided more substantial support for the theory of EBV infection as a possible trigger of MS.

Harvard study

In a landmark study published in the journal Science, a team of researchers at the Harvard T.H. Chan School of Public Health, in Boston, identified the most definitive link between EBV and MS risk to date. The team found the virus increases the risk of developing MS by 32 times, placing EBV as the leading risk factor for the neurodegenerative disease.

Through a 20-year collaboration with the U.S. military, researchers tracked the long-term health of more than 10 million active-duty service members. Participants underwent blood screening at the start of their military service and every two years thereafter.

The analysis ultimately included 801 individuals who developed MS and 1,566 service members who did not. The control group without the disease were matched to the MS group members based on characteristics such as age, sex, and military branch. Blood samples were tested for the presence of antibodies against EBV.

The results showed that 800 of the 801 people with MS had been infected with EBV before MS onset.

Among the 35 MS cases and 107 healthy people who were EBV-negative at the start of their service, MS was still preceded by EBV infection in all but one individual (97%). In contrast, 57% of non-MS cases were later infected with the virus.

MS symptoms emerged a median of 7.5 years after the estimated time of EBV infection. Levels of neurofilament light chain, a biomarker of nerve cell damage, were increased in service members who later developed MS — but only after they became infected with EBV. This result provided additional support that EBV precedes even early signs of neurodegenerative disease.

The team also showed infection with other viruses, including the similarly transmitted cytomegalovirus, were not associated with a risk of developing MS.

Stanford medicine study

Just weeks after the Harvard study was published, Stanford scientists identified a mechanism, called molecular mimicry, by which EBV might lead to MS.

In the study, published in the journal Nature, this team reported an EBV protein, called EBNA1, is structurally similar to the human body’s own GlialCAM protein. GlialCAM is produced by oligodendrocytes — the cells mainly responsible for producing myelin, the protective sheath surrounding nerve cell fibers that is the target of autoimmune attacks in MS.

Tests showed patients’ immune B-cells were producing antibodies against EBNA1 that were cross-reactive and able to also bind to GlialCAM in a similar manner due to the resemblance of the two proteins.

Based on these findings, the researchers developed a working model of how EBV causes MS. They hypothesized that first, B-cells that come in contact with EBV will produce antibodies against the EBNA1 protein in an effort to suppress the virus. These antibodies then undergo alterations that increase their ability to attack GlialCAM, in turn leading to an aberrant autoimmune attack on the healthy nervous system.

While a causative role for EBV in MS has become increasingly clear, the virus alone is not likely to be sufficient to cause the disease. Other genetic and environmental risk factors, such as smoking or the HLA-DRB1*15:01 gene variant, likely interplay with EBV to cause MS.

How do you become infected with EBV?

EBV is most commonly transmitted from the bodily fluids, especially the saliva, of an infected person. Therefore, the virus is spread easily through activities such as kissing, sharing food or drink, and contact with contaminated items such as utensils, toothbrushes, or toys children have drooled on. The virus likely survives on these objects for at least as long as they remain moist.

Additionally, EBV can be spread through blood and semen during sexual contact, via blood transfusions, or during organ transplants.

When infected with Epstein-Barr, a person may be contagious for weeks, even if there are no overt symptoms of the virus.

Tests used to detect EBV infection

Laboratory testing can help to determine if a person has had a recent or past EBV infection.

In response to a potentially harmful substance like a virus, a person’s immune system generates antibodies against the foreign invader. Those antibodies will continue to live in the body after an active infection, and can be used as a proxy measure of a prior infection.

The most common way of identifying a history of EBV infection is through a blood test for antibodies against certain proteins of the EBV virus.

Different antibodies can provide information about how recent the infection might have been. For example:

• viral capsid antigen (VCA): these antibodies usually emerge early during EBV infection. One type of VCA, called IgM, disappears within four to six weeks, while another one, called IgG, will decline but persist for a person’s whole life. The presence of VCA-IgM, or high levels of VCA-IgG, thus indicates a new or recent infection.
• EBV nuclear antigen (EBNA): these antibodies are not seen during acute infection but begin to emerge 2–4 months later and persist for the rest of a person’s life. In combination with VCA-IgG, they indicate a past infection that occurred several months to years earlier.

Can you prevent EBV infection?

There is no vaccine to prevent EBV infection. As with other viruses, the best ways to protect oneself against infection are to avoid kissing people known to be infected with EBV, or sharing food and drinks, or other personal items belonging to them.

Investigational MS therapies targeting EBV

With the emergence of landmark studies more strongly linking the Epstein-Barr virus to MS, there has been an increased focus on developing therapies that might prevent disease progression by targeting EBV.

ATA188

Atara Biotherapeutics is developing ATA188 for the treatment of progressive and relapsing forms of MS. Normally, T-cells are involved in regulating immune responses, but EBV-infected immune cells escape this regulation and proliferate excessively.

ATA188 is an immunotherapy containing T-cells with the capacity to selectively identify and destroy EBV-infected cells in the brain and spinal cord.

The two-part Phase 1/2 EMBOLD trial (NCT03283826), launched in 2017, is evaluating the safety and efficacy of the treatment in adults with primary or secondary progressive MS at clinical sites in North America and Australia.

Atara also has reported plans for Phase 2 trials in patients with relapsing-remitting MS and clinically isolated syndrome, as well as Phase 3 trials for progressive MS patients.

Earlier this year, Tevogen Bio also announced plans to develop its own T-cell therapy targeting EBV.

PAS002

PAS002 is an investigational vaccine being developed by Pasithea Therapeutics. It is based on data from the Stanford study, which reported the immune system’s confusion between EBV and the myelin protein GlialCAM as the underlying mechanism of the autoimmune attack in MS.

This vaccine is designed to promote immune tolerance to GlialCAM by helping the body recognize it as self and not as a foreign invader. PAS002 delivers GlialCAM’s DNA to the body, which then uses it to produce its own GlialCAM protein. The hope is that by teaching the immune system to recognize GlialCAM as harmless, the mistaken autoimmune attack against it will be prevented.

This treatment is now in preclinical development, with data showing early efficacy.

Vaccines to prevent EBV infection

The development of a vaccine to prevent EBV infection is of significant interest, but may be hindered by several challenges. Two clinical trials are underway to evaluate investigational EBV vaccines.

The National Institutes of Health (NIH) launched a Phase 1 trial (NCT04645147) to test its experimental vaccine, gp350-Ferritin, which targets a protein found on the surface of the virus and in virus-infected cells. The trial aims to assess the vaccine’s safety, and its ability to produce an immune response against EBV in healthy young adults, ages 18–29.

Moderna also launched a Phase 1 trial (NCT05164094) to test its candidate vaccine, called mRNA-1189. This vaccine uses similar mRNA technology to that used for the company’s COVID-19 vaccine. Like the NIH study, this trial is testing the vaccine’s safety and ability to induce an immune response in healthy adults, ages 18–30.

What other diseases are associated with EBV?

EBV has been linked to a number of other autoimmune conditions, including:

• systemic lupus erythematosus (SLE);
• rheumatoid arthritis;
• Sjögren’s syndrome;
• celiac disease;
• type 1 diabetes;
• inflammatory bowel disease; and
• juvenile idiopathic arthritis.

The virus also is closely associated with certain types of cancer, such as:

• Hodgkin lymphoma;
• Burkitt lymphoma;
• nasopharyngeal carcinoma; and
• stomach cancer.

Is there a link between MS and any other viruses?

Several viruses have been associated with MS over time — including measles and the varicella-zoster virus, which causes chicken pox and shingles — but for most, there is not enough evidence to definitively establish a link. Notably, in the landmark Harvard study suggesting EBV as a risk factor for MS, other common viruses were not associated with a similar risk.

Two families of viruses appear to have the most plausible support linking them to MS: herpesvirus (of which EBV is one type) and human endogenous retroviruses (HERVs).

Human Herpes Virus 6 (HHV-6)

A number of studies have found HHV-6, another virus in the herpesvirus family, may also be involved in MS risk or relapses. As with Epstein-Barr, antibodies against HHV-6 — specifically a variant called HHV-6A — are present at higher levels in MS patients than in healthy people. It seems that having antibodies against both EBV and HHV-6A may further elevate the risk of developing MS.

HHV-6 also has been suggested to act as a trigger for relapses in MS patients. A study found that certain HHV-6 antibodies are at their highest in MS patients two weeks before a relapse occurs. Other studies also have linked HHV-6 antibody levels to inflammation, disability, and clinical relapse.

HERVs

HERVs are present in the genome of all vertebrate animals, and represent ancient infections occurring in ancestors that have been passed down through genes in the genetic code. While typically inactive or non-functional, HERVs can be reactivated under certain conditions.

MS has been linked to increased HERV expression, and a number of studies suggest the virus can potently modulate the immune system, contributing to MS autoimmunity. Evidence also shows EBV can activate HERVs, which also could play a role in the relationship between EBV and MS.

MS and infection risk

A large body of evidence, that includes studies in the National Library of Medicine, suggests MS patients may generally be at a greater risk of infections than individuals in the general population. People with MS also may be at a higher risk of more serious consequences, including hospitalization after infection.

Certain immune-suppressing disease-modifying MS therapies might also further increase the risk of infections in MS patients.

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