Table of Contents
Introduction
Dr. Faustman, MD, PhD is an immunobiologist at Massachusetts General Hospital who has long worked with the BCG vaccine. This is a vaccine which has been around for decades and is used primarily to vaccinate against tuberculosis. It’s not used in the US because of our low TB rates which have been achieved primarily through sanitation and public health measures. During the current coronavirus pandemic, some epidemiologists have noticed that countries with mandatory BCG vaccination policies have suffered less severe SARS-CoV-2 outbreaks both in magnitude and severity. This recognition fits with the knowledge of the vaccine as having properties for modulating the immune system in such a way as to protect against pathogens, autoimmune conditions, and even certain cancers, though the vaccine itself is made from "weakened" mycobacterium. Below is a question and answer that was conducted electronically between myself and Dr. Faustman. I was fortunate to have her answer these questions. I have several other more detailed questions that I hope to have the chance to discuss with her in the future.
For more information, take a look at this document on Dr. Faustman’s website which provides the rationale for their research of the BCG vaccine as it relates to the Covid-19 pandemic.
Dr. Faustman can be found on Twitter here.
What is the BCG vaccine?
BCG is a live, attenuated bacterial vaccine that contains the avirulent tuberculosis strain Mycobacterium Bovis. It has historically been given to protect against tuberculosis and, since its introduction in 1921, has been the most widely administered vaccine in the history of medicine. BCG is considered to be extremely safe, is on the World Health Organization’s Model List of Essential Medicines for adults and children, and is given to roughly 100 million children per year globally. BCG is also one of the most affordable medicines, costing less than a dollar a dose in many parts of the world. BCG, however, is not one vaccine, but the name given to multiple M. Bovis strains now produced globally, and all based on the original vaccine developed at the Pasteur Institute over a century ago. The differences in the strains, although well documented, require further study, and are one of the reasons why trial design requires consideration in the strain of BCG vaccine.
Where did the BCG vaccine come from?
Our strain is made in Japan. There are multiple strains based on the original strain developed at the Pasteur Institute.
How does the BCG vaccine work?
Epidemiological studies provide further support by showing that vaccination with certain live vaccines is associated with lower rates of disease due to unrelated pathogens. For example, BCG vaccination in newborn children provides protection not only against tuberculosis, but has also been associated with a reduction in respiratory tract infections, neonatal sepsis, and all-cause mortality. It has been also shown that BCG vaccination in healthy adults induces long lasting immunity and protection from respiratory tract infections. Recently, it has been demonstrated that BCG vaccination alters the epigenetic program of hematopoietic stem cells resulting in monocyte-derived macrophages that provide enhanced protection against pulmonary infection. Multiple clinical trials have demonstrated the beneficial "off target" effects of BCG as it relates to infections. New and very preliminary data suggests large-scale national BCG vaccination programs are associated with reduced COVID-19 morbidity and mortality across borders and age groups.
What is the "innate memory response" or "trained immunity," as it is sometimes called?
Over the last century, the new field of innate memory or innate reprogramming or priming has emerged. Interestingly, this was first observed in plants that only have an innate immune system and it was discovered that plants after one type of exposure could, from generation to generation, pass on the immunity to offspring and the priming protection was often unrelated to the primary challenge.
The basic concept has expanded in vertebrates with many observations that one infectious exposure or vaccination can alter the subsequent defensive immune response in ways unrelated to the primary pathogen. This "trained immunity" has emerged based on data that certain infectious organisms modulate the host metabolism and immune systems by acting on DNA methylation, and even control host phosphorylation patterns for protein activation. This has created a more detailed understanding of the immunological underpinning of BCG or other organisms in autoimmunity and immune system modulation. Trained immunity is a form of broad immune memory, induced by epigenetic reprogramming of gene expression and cell physiology, that confers non-specific, protective effects from certain infections. Indeed, this phenomenon appears to be behind the broad beneficial effects of BCG vaccination, extending even to autoimmunity not just additional unrelated infections.
What is the evidence that this vaccine might work for SARS-CoV-2?
Historically, vaccine design has involved the identification of a perfect antigen that generates long-term T and B cell memory responses and provides protective immunity upon a reencounter with the same pathogen. However, this approach takes months to years to develop and has yet to lead to a successful vaccine against coronaviruses (e.g. SARS or MERS). However, the vast majority of species (e.g. plants, invertebrates) rely on innate immunity for host defense, including immunological memory generated independent of adaptive immunity. Importantly, the mechanisms involved in innate memory response (called trained immunity) has been shown to confer protection against many infectious diseases.
Epidemiological studies provide further support by showing that vaccination with certain live vaccines is associated with lower rates of disease due to unrelated pathogens. For example, BCG vaccination in newborn children provides protection not only against tuberculosis, but has also been associated with a reduction in respiratory tract infections, neonatal sepsis, and all-cause mortality. It has been also shown that BCG vaccination in healthy adults induces long lasting immunity and protection from respiratory tract infections. Recently, it has been demonstrated that BCG vaccination alters the epigenetic program of hematopoietic stem cells resulting in monocyte-derived macrophages that provide enhanced protection against pulmonary infection. Multiple clinical trials have demonstrated the beneficial "off target" effects of BCG as it relates to infections. New and very preliminary data suggests large-scale national BCG vaccination programs are associated with reduced COVID-19 morbidity and mortality across borders and age groups.
Is the vaccine safe for adults?
The BCG vaccine is the safest vaccine ever given, though it is not recommended for immunocompromised individuals.
What are all of the potential benefits?
The BCG vaccine, in addition to the potential benefits described above, may also prevent various forms of autoimmunity.
Why don’t we currently use this vaccine in the United States?
The US has very low rates of tuberculosis, so there is no universal BCG vaccination policy.
What are the obstacles to using this vaccine now?
Funding for controlled trials is needed to show whether or not this vaccine will work for infections like COVID-19.
What can people do to help speed clinical trials?
Get involved. We need help funding trials, http://faustmanlab.org
Summary
The BCG vaccine is an inexpensive, very safe, time-tested, and promising vaccination that might be useful for this and future pandemics. It has also been demonstrated to be useful in bladder cancer, and may be beneficial for some Type 1 Diabetics. There are some remaining questions in my mind that I’d like to have answered before I personally would want to take this vaccine.
Remaining Questions
- Despite the high level of safety, there must be some potential dangers or downsides to the vaccine, what are these and how could an individual adult assess their own risk?
- With respect to COVID-19, how do we know that the correlation between countries with BCG vaccination policies and COVID-19 cases is related to the BCG vaccine itself? Could the presence of a BCG vaccine policy be a marker for something else, such as a factor related to environmental exposures, microbiome, other immune factors, or some societal or cultural factor?
- Is the vaccine effective if given to adults? Most countries use the BCG vaccine primarily in infants and young children, and usually not over age 35.
- If it is effective in adults, how quickly might it work against an acute infection such as COVID-19?