Live-Attenuated Vaccines and Trained Immunity

One of the hypothesis for why children appear to have less severe cases of COVID-19 than adults is that childhood vaccines may provide general immunity to all pathogens by boosting the innate immune system. In this post, I’m going to discuss the concepts of trained immunity and non-specific vaccine protection.

Why Consider Live-Attenuated Vaccines?

Live-attenuated vaccines contain a pathogen that has been weakened so that it doesn’t replicate as efficiently or cause disease in humans. Common live-attenuated vaccines given to children include the vaccines for measles, mumps, and rubella (MMR); rotavirus, which causes diarrhea and vomiting; intranasal influenza; and chickenpox. These pathogens were modified in a laboratory to replicate poorly in humans, or they were made less virulent by knocking out some genes. Live-attenuated vaccines preserve the structure and function of the pathogen to induce the strongest immune response in humans without causing a disease. There is evidence that some live-attenuated vaccines can provide non-specific protection against many pathogens. This means that they don’t just protect you against the pathogen in the vaccine, but they also prepare your immune system for infections by a wide variety of pathogens.

Live-attenuated vaccines are the closest simulation to an actual immune response that your body gets. The pathogen is weakened, but it is still able to infect and replicate inside cells, which is more likely to stimulate both strong humoral (antibody-based) and cell-mediated immunity. The vaccine stimulates antibodies against many viral or bacterial proteins, and the vaccine pathogens enter through the normal infection route, closely mimicking an infection.

This stimulates a very important branch of immunity called mucosal immunity. The mucosa are specialized tissues that line your respiratory, digestive, and genitourinary tracts to protect you from dehydration and microbes that enter through these openings. Live-attenuated pathogens can also be transmitted between people like how a virulent pathogen spreads, which promotes herd immunity. So even people who are not vaccinated (but really, you should get vaccinated) can acquire the vaccine through human to human transmission.

The Innate Immune System (Again)

Here, we’re going to make a detour to revisit the branches of the immune system. When a pathogen first enters the body, receptors called pattern-recognition receptors are specialized for recognizing foreign invaders. These receptors are part of the innate immune system and are therefore non-specific, which means that they don’t distinguish between pathogens, but only that they are foreign. When DNA or proteins from microbes (bacteria, viruses, and fungi can all cause diseases in humans) are recognized by these receptors, the receptors initiate inflammation and signal macrophages to engulf invaders. There are many classes of pattern recognition receptors, which recognize different components of microbes, such as DNA modifications not present in humans and carbohydrates found in their cell walls. In the figure below, a macrophage recognizes a virus and then engulfs it. The virus is contained inside a compartment called a phagosome, where enzymes break it down, typically with acid.

Phagocytosis

An important cytokine for fighting viral infections is called interferon (IFN). These interfere (hence the name) with viral replication, but also activate immune cells. Interferons are also typically responsible for the symptoms you experience when you’re sick, including fever and body aches. This is why you get similar symptoms when sick with different viruses: the sick feeling is caused by your body’s immune response, not by the virus itself. In the early stages of infection, many viruses turn down the host interferon response, allowing the virus to replicate and spread unchecked because the immune response is dampened. Interferons are secreted non-specifically against all viruses when the body recognizes an infection. A strong immune response soon after infection can prevent the infection from spreading and worsening.

Trained Immunity

The concept of trained immunity is relatively new and refers to immunological memory in the innate immune system. Most of us think of only the adaptive immune system having memory because it produces memory B and T cells that remain in the blood long after an infection has been cleared. In the event of future reinfections, these memory cells “remember” that pathogen and can mount an immune response faster than the first one. Indeed, the goal of vaccines is to stimulate the adaptive immune system and protect the body from reinfections.

However, plants 1 and invertebrates 2 do not have adaptive immune systems, and yet, they still react faster to pathogens they’ve already seen. In addition, laboratory mice with severe combined immunodeficiency due to the absence of B and T cells have some protection from subsequent infections, which must be independent of the adaptive immune system 3 .

Trained immunity is a transient state and does not modify the genes of an organism. There are certain modifications that are related to genes called epigenetic modifications. The prefix “epi” means that the genes themselves aren’t changed, but something on or around them is.

Histone Proteins and DNA The genetic material of plants and animals is organized into bundles called chromosomes. These bundles are made of our DNA tightly wrapped around histone proteins and are the reason that our 3 meter long DNA fits inside microscopic cells -- the DNA is bunched up very tightly to make it fit into a smaller space. However, the proteins needed to make mRNA from DNA can only get to the DNA if it’s not wound too tightly with the histones. Genes that are very active in certain cells are less tightly wound (more open) so that they can make mRNA more easily.

Chemical modifications called methylation and acetylation regulate how accessible regions of the genome are. These changes don’t alter the genetic code – the sequence of the 4 bases in DNA – and so they aren’t passed from parents to children. But the patterns of methylation and acetylation change based on the chemical environment of each cell. A group in the Netherlands has shown that macrophages (pathogen engulfers) undergo certain epigenetic changes when stimulated with the live-attenuated Bacille Calmette-Guérin (BCG) vaccine for tuberculosis that allow them to mount stronger immune responses against future infections 4 .

Vaccines that May Induce Trained Immunity

In most of the world besides the United States, Canada, Australia, and Western Europe, the tuberculosis vaccine is administered to newborn babies. This vaccine was developed in the early 1900s by two French microbiologists at the Pasteur Institute, Albert Calmette and Camille Guérin, and was first administered to infants in 1921. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is rod-shaped, so it is known as a bacillus species. Therefore, the vaccine is called Bacille Calmette-Guérin. The BCG vaccine is effective at protecting infants from the most dangerous forms of tuberculosis that spread throughout the body and attack the brain. However, the vaccine has variable efficacy in adults.

This unreliable efficacy is not fully understood. Some scientists speculate that naturally-occurring less virulent strains of Mycobacteria could interfere with the effectiveness of the BCG vaccine 5 . As the vaccine is given to more people throughout the world, the bacteria accumulate mutations as they naturally replicate. This means that the strains in the vaccines may not be identical and could affect vaccine efficacy. A study of mice given past BCG formulations from different countries showed that BCG vaccines had different levels of virulence and efficacy 6 . Today, all BCG vaccines are the BCG-Danish strain.

Bacteria contain a lot of proteins and sugars (carbohydrates) in their cell wall, the thick layer around their cell membrane that protects the bacteria and allows them to maintain their shape. Many of these microbial components are recognized as foreign by human cells by binding to pattern recognition receptors, and an innate immune response will be initiated. Components found in many bacteria like β-glucan and lipopolysaccharides have also been shown to affect macrophages similar to the manner in which BCG does.

There is anecdotal evidence that the oral polio vaccine (OPV) may also have non-specific effects similar to those of BCG. This comes from interviews with Konstantin (Kostya) Chumakov, a director of vaccine development at the FDA 7 . Chumakov, who grew up in the former Soviet Union, described that children given OPV had a lower incidence of influenza, and there is other evidence that OPV reduced mortality rates in children in Guinea-Bissau in West Africa 8, 9, 10 .

Albert Sabin’s Oral Polio Vaccine

Another live-attenuated vaccine given throughout the world is the oral polio vaccine (OPV), which was developed by Polish researcher Albert Sabin in the 1950s. At the same time in the United States, Jonas Salk developed the inactivated polio vaccine (IPV), which is given by injection. OPV provides greater population protection than IPV, and it can be given orally (through the mouth), so it is much easier and cheaper to administer than IPV, which must be injected by a trained healthcare professional.

Salk and Sabin


Therefore, the Global Polio Eradication Initiative administers OPV in countries with endemic poliovirus. Unfortunately, this program has had to be halted due to the COVID-19 pandemic. In impoverished areas, health care workers must go to people’s homes and immunize children, which would promote SARS-CoV-2 spread. However, if OPV is conclusively shown to provide protection against other unrelated pathogens, then it could justify restarting the Global Polio Eradication Initiative to protect against both poliovirus and SARS-CoV-2.

The caveat here is that OPV carries a slight risk. Poliovirus is a type of enterovirus, meaning that it replicates in the digestive tract (entero = intestine). When children are immunized with OPV, the live-attenuated virus is able to replicate in the digestive tract (unlike IPV, which can not replicate), and poliovirus is excreted and enters the environment. This poliovirus is more virulent than the virus used for vaccination because as the virus replicates, it removes the mutations that Sabin screened for to attenuate it in the first place. This excretion of viruses makes OPV more effective because people who didn’t receive OPV can still be immunized through environmental exposure to small amounts of the virus. However, vaccine administration has also been associated with approximately 1 case of paralysis per 2.9 million vaccine doses given, which is less than a 0.00004% risk.

Since 1988 when the Global Polio Eradication Initiative began, the number of annual poliovirus infections has decreased from 350,000 to fewer than 50 cases in 2018, attesting to the efficacy of OPV 11 . Despite the risk of paralysis caused by the vaccine, there is a far greater risk for unimmunized children dying of poliovirus acquired naturally. Approximately 0.5% of poliovirus infections cause paralysis, and 5-10% of paralyzed children die because their breathing muscles become paralyzed 12 . With all the results taken together, the World Health Organization has deemed OPV the vaccine of choice for the eradication program. The oral polio vaccine is only given in countries with endemic polio, and the inactivated poliovirus vaccine is given everywhere else. As polio incidence drops in countries, the World Health Organization switches vaccination from OPV to IPV.

Being Cautious about Correlations

A preprint from late March on medrxiv.com, a server for papers that have not yet been peer-reviewed, reported a positive correlation between countries without universal BCG vaccination policies and COVID-19 deaths 13 . However, correlation DOES NOT MEAN causation. There are numerous other factors influencing COVID-19 deaths, particularly testing availability, access to adequate health care, and population demographics. Developing countries (which have universal BCG vaccination policies) tend to have younger populations than developed countries, and we know that age generally increases the risk of death from COVID-19. Developing countries also tend to have lower access to SARS-CoV-2 testing, so both cases and deaths can go unnoticed.

In addition, the pattern doesn’t hold everywhere. Iceland, for example, does not have a universal BCG vaccination policy, but has had fewer than 2,000 COVID-19 cases and fewer than 50 deaths, as of May 20, 2020 14, 15 . It is clear that social distancing, personal protective equipment (masks, gloves, barriers between people), and a robust system for testing and isolating infected individuals and their contacts are more important than vaccination history for reducing COVID-19 infections and deaths.

Although BCG may provide non-specific protection against SARS-CoV-2 and other pathogens, it is not clear how long the protection will last in humans. Exposures to other pathogens and non live-attenuated vaccines can actually reverse the trained immunity state 16, 17 . BCG is administered close to birth, and it is not yet known if the non-specific immune effects persist decades later in adults. Mihai Netea’s group at Radboud University in the Netherlands found that BCG-induced epigenetic changes also occur in bone marrow stem cells, which give rise to immune cells 3 . Epigenetic changes can be long-lived in these self-renewing stem cells and can change the overall macrophage population.

Concerns about Using Live-Attenuated Vaccines for Trained Immunity

BCG is not recommended for immunocompromised individuals because it can make them susceptible to the disease. With around 1-2 million new HIV infections each year, vaccine regimens for immunocompromised populations become complicated because live-attenuated vaccines are likely to harm, rather than help, them. Using microbial components, such as carbohydrates and lipids found in their cell walls, is safer than using the entire pathogen. To make a vaccine specially designed to induce trained immunity, we can choose cocktails of components to stimulate multiple toll-like receptors of the innate immune system.

Current estimates put the longevity of trained immunity at around 1 year. An interesting question is whether we can boost current vaccines, such as the annual flu shot, with BCG or other similar adjuvants. The innate immune system could be boosted annually, potentially reducing people’s susceptibility to all manner of infections. However, there is the risk that keeping the innate immune system on high alert could cause excessive inflammation and increase the risk of allergies and autoimmune diseases. Our immune systems generally know not to react to harmless antigens in food and beneficial bacteria in our digestive tracts, called immunological tolerance, but long-term trained immunity could cause problems for this. Bacterial adjuvants are highly immunogenic and can cause damaging hyperinflammation, but some bacterial proteins have been modified to eliminate their toxicity.

Conclusion

There have been pushes by scientists to test if certain live-attenuated vaccines can provide broad protection against pathogens, including SARS-CoV-2. Those under primary consideration are BCG and OPV. Clinical trials have begun for BCG in at least 3 different countries – the Netherlands, Australia, and the United States 18, 19, 20 . The dose already approved for human dose is being given to healthcare workers to see if those that receive the vaccine are at lower risk of getting COVID-19 and having poor outcomes.

Interestingly, Mihai Netea conducted a trial in 2014-2015 in the Netherlands on the effects of BCG on the efficacy of the flu vaccine 21 . In a randomized trial of 40 healthy male participants, they found that BCG increased antibody production in response to the trivalent 2013-2014 flu vaccine 22 . This may not hold for all vaccines or even all strains of the flu, but it is a promising result. Kostya Chumakov and others are currently pushing for trials testing the non-specific protection of OPV, but none has been initiated yet.

Widespread use of live-attenuated vaccines carries some risks. They could be harmful to severely immunocompromised individuals, such as people who are infected with HIV or are taking immunosuppressants because of organ transplants. Live-attenuated vaccines have not been extensively studied in the elderly because they are typically given to young children. However, due to the possibility of live-attenuated vaccines such as BCG providing non-specific protection, they need to be studied more fully in older animals and people. This is especially important given that BCG-like adjuvants could be administered to everyone to improve the efficacy of common vaccines like the flu vaccine and provide temporary protection against SARS-CoV-2.

Other vaccine types are safer for people who can not receive live-attenuated vaccines because there are no infectious particles in the other types. Although it is possible for live-attenuated viruses to be transmitted to immunocompromised people from those who were vaccinated, the risk is relatively low unless you’re in direct contact (family member or caregiver) with an immunocompromised person. To prepare for future epidemics and improve our fight against existing ones, we need a variety of treatments and vaccines against the immense diversity of microbes on the Earth. And we must act proactively to develop vaccination platforms that can be applied to many pathogens.

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