Vaccine Innovations — Past and Future | NEJM
Saint Louis University Researchers Develop New Model By Leveraging An Old Vaccine
Each year, tuberculosis (TB) kills more people than any other infectious disease, and Saint Louis University researchers are working to reduce the disease's impact via vaccine development.
Director of the Saint Louis University Center for Vaccine Development Daniel Hoft, M.D., Ph.D., works with colleagues in the lab. SLU File Photo.
Despite TB's wide reach and some lost progress during the COVID-19 pandemic, researchers believe it is possible to eradicate TB through advances in vaccine development and public health. To cross the finish line, scientists must find ways to test new vaccines rapidly to prevent TB infections more effectively.
In a paper published in The Journal of Infectious Diseases, Daniel Hoft, M.D., Ph.D., director of the Saint Louis University Center for Vaccine Development, and colleagues from SLU, Emory University School of Medicine, The Emmes Company, LLC, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and New York University Grossman School of Medicine, report a promising new approach to speed up vaccine testing for TB.
Hoft, who also serves as professor and chair of infectious diseases, allergy, and immunology at the Saint Louis University School of Medicine, sought data that could only be gathered by challenging the human immune system directly. This approach, Hoft hypothesized, could provide answers to some TB unknowns. For example, TB animal models do not fully mimic how the bacteria behave in people, and vaccine developers do not have well-defined data about what TB immune responses offer optimal protection against the bacteria.
To test new vaccines, infectious diseases researchers sometimes conduct human challenge studies to quickly learn about how well a vaccine candidate works against an infectious disease, such as influenza. In these studies, researchers first deliver an investigational vaccine or placebo to separate groups of healthy volunteers, and then intentionally infect study participants with a flu virus, all in carefully controlled settings and under close medical supervision, to determine whether the investigational experimental vaccine provides protection compared with the control group. This approach can be instrumental in generating data supporting the approval of novel vaccines.
Mycobacterium tuberculosis, the bacteria that cause TB, however, is too dangerous for human challenge with the fully pathogenic bacteria. The team needed to find another, safer way to challenge the human immune system to find answers to their questions.
Hoft found a workaround in the Bacillus Calmette-Guérin (BCG) vaccine.
The most widely used vaccine in history, with more than 4 billion doses given to patients since 1921, the BCG vaccine contains a live but weakened version of the TB bacteria. The BCG vaccine is given to newborns to reduce their TB risk, but it is less effective against pulmonary TB and often wanes in effectiveness, providing little to no protection in adults.
With the BCG vaccine, Hoft saw a chance to gather data about TB in a human study without the risk of exposing participants to full-strength M. Tuberculosis bacteria. To test this idea, the researchers gave 92 healthy adults the BCG vaccine, with participants receiving one of four different doses.
With participants' immune response to the BCG vaccine serving as a proxy for their exposure to a true infection, the researchers gathered much-needed data about how the immune system responds when it encounters TB.
The team applied a battery of analysis methods to samples collected from the BCG challenge sites and blood, looking for associations between BCG at the injection site, and immune responses as well as gene expression changes in blood.
The findings open up new doors for TB vaccine development.
"Our findings are important for two reasons," Hoft said. "First, this approach could enable us to screen new TB vaccines early in the pipeline and prioritize the most promising concepts, saving time and money. Second, we have a model to better determine what a new vaccine needs to do to protect against TB. We will be able to identify biomarkers indicating whether new vaccines could better protect someone against TB."
Among the findings that will help vaccine developers as they create new vaccines:
Researchers hope this new model will help advance our understanding of why men and women have different levels of general immunity.
Hoft is enthused by the findings, which he says could provide a road map for future TB vaccine testing.
"The BCG human challenge model is a promising approach for studying TB immunity," Hoft said. "The new data will facilitate the vaccine development process, allowing us to make progress toward our ultimate goal of eradicating TB."
The content in this press release is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Should My Daughter Have The BCG Jab?
BCG (Bacillus Calmette - Guerin) vaccine is made from a treated (attenuated) live strain of bacterium derived from Mycobacterium bovis, a bacterium which typically causes tuberculosis (TB) in cattle but can infect humans. The vaccine was introduced by Calmet and Guerin in France in 1921. It was originally given by mouth but was not successful. It was not until 1927 when Wallgren introduced intradermal (injected into the skin) BCG vaccination in Sweden that it became a striking success in the fight against TB.
In the UK the BCG vaccine is routinely offered to all children between 12 and 14 years of age - just as your daughter has been offered. Some children will already be immune to TB, either following earlier infection with TB (such infection can be with a milder strain of TB and pass unnoticed), or following previous vaccination (for example as a baby if living in a high risk area or under a different country's immunisation schedule). A few children may have active TB infection. When a person has had TB infection or received the BCG vaccine he develops hypersensitivity to Mycobacterium tuberculosis, the bacterium which usually causes TB in humans.
Part of the immunisation procedure involves testing all children before giving them the BCG vaccine to see if they are already sensitised. This test will be offered to your daughter. It cannot be done if she has received a live vaccine within the previous four weeks as her response to the test may be reduced. A protein called Tuberculin is extracted from the Mycobacterium tuberculosis and is highly purified. A drop of the tuberculin in placed on the inner surface of your daughter's forearm. A sterile set of six tiny needles in a circle of 6mm is then pushed or fired from a spring loaded 'gun' into her skin over the tuberculin so as to penetrate her skin by 1-2 mm depth. This method is called the Heaf teat and is the one commonly used in this country as it is not painful and is quick and easy to perform in a standardised way.
Your daughter's arm is examined five to seven days later and the results are graded according to the strength of response. If there is no response the result is negative. If five or six individual puncture marks are seen or felt the reaction is called Grade 1. Positive reactions are graded two to four and are a sign that she has already been sensitised to TB.
If your daughter's Heaf test is negative or Grade 1 she is not immune to TB and requires the BCG vaccination. This is given as an injection into the skin itself (an intra dermal injection). Within two-six weeks a small swelling appears at the injection site. This turns into a raised lump or ulcer about 10mm across which heals in six to 12 weeks. She can put a dry dressing over the skin if it produces a discharge but she should allow air to get to the skin. Once the skin heals she will be left with a characteristic small round scar which is evidence of BCG vaccination for the rest of her life.
If your daughter's Heaf test is positive she will not be given the BCG vaccination. She will be checked to see if she has any scars from previous BCG vaccinations (although you do not mention she had earlier BCG vaccine). She will be referred to the local chest specialist who may do a chest X ray and further tests to make sure she does not have active Tuberculosis. If these tests are clear it means that she is already immune to TB and will not need the vaccine.
In addition to your daughter not needing the vaccine if she has a positive Heaf test, there are several other reasons why she may not be able to have the vaccine:
1. If she is suffering from an acute illness the vaccine will be postponed until she is well.
2.If she has reduced immunity for example due to being HIV positive or if she had a malignant condition such as leukemia or lymphoma or is receiving high dose steroids, radiotherapy or chemotherapy she cannot be given BCG because it is a live vaccine and could cause her to develop a form of TB illness. BCG is postponed for at least three months after stopping steroids and six months after stopping chemotherapy.
3.If she suffers with any condition causing generalised skin infection or inflammation she cannot receive the vaccine as it relies on being injected into the skin. If she suffers with eczema the vaccine needs to be injected into a site on her body free from eczema.
4. If she has had another live vaccine, eg rubella, measles, yellow fever or typhoid, BCG cannot be given until at least three weeks later. However it can be given at the same time as any of these vaccines.
5. Although probably not relevant to your daughter I should mention that pregnancy is another reason to avoid live vaccines such as BCG as they can cause infection in the fetus.
You ask about side effects of the BCG vaccine. Like any vaccine it can produce discomfort at the injection site in her arm and mild fever or malaise. Serious reactions with BCG are uncommon. If there is a reaction at all it is usually a prolonged ulcer or abscess at the injection site. This can be a result of the injection having been given too deep, ie below the skin, instead of into the skin, which is why people giving the injection have to be skilled at performing it correctly. Severe allergy (anaphylaxis) to BCG is very rare. It happens within minutes of receiving the vaccine and needs immediate treatment, usually with adrenalin which is always kept on site by the medical team giving the vaccine.
I would recommend that if your daughter is fit and well she has the BCG vaccine as tuberculosis is an illness which is very much around and possibly on the increase in this country.
We recommend readers seek personal medical attention in appropriate circumstances
To Build Better Tuberculosis Vaccines, Researchers Develop New Model By Leveraging An Old Vaccine
Each year, tuberculosis (TB) kills more people than any other infectious disease, falling out of the top spot only temporarily during the COVID-19 pandemic.
Despite TB's wide reach and some lost progress during the COVID-19 pandemic, researchers believe it is possible to eradicate TB through advances in vaccine development and public health. To cross the finish line, scientists must find ways to test new vaccines rapidly to prevent TB infections more effectively.
In a paper published in the Journal of Infectious Diseases, Daniel Hoft, M.D., Ph.D., director of the Saint Louis University Center for Vaccine Development, and colleagues from Saint Louis University, Emory University School of Medicine, The Emmes Company, LLC, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and New York University Grossman School of Medicine, report a promising new approach to speed vaccine testing for TB.
Hoft, who also serves as professor and chair of infectious diseases, allergy, and immunology at the Saint Louis University School of Medicine, sought data that could only be gathered by challenging the human immune system directly. This approach, Hoft hypothesized, could provide answers to some TB unknowns. For example, TB animal models do not fully mimic how the bacteria behaves in people, and vaccine developers do not have well-defined data about what TB immune responses offer optimal protection against the bacteria.
To test new vaccines, infectious diseases researchers sometimes conduct human challenge studies to quickly learn about how well a vaccine candidate works against an infectious disease, such as influenza. In these studies, researchers first deliver an investigational vaccine or placebo to separate groups of healthy volunteers, and then intentionally infect study participants with a flu virus, all in carefully controlled settings and under close medical supervision, to determine whether the investigational experimental vaccine provides protection compared with the control group. This approach can be instrumental in generating data supporting the approval of novel vaccines.
Mycobacterium tuberculosis, the bacteria that cause TB, however, is too dangerous for human challenge with the fully pathogenic bacteria. The team needed to find another, safer way to challenge the human immune system to find answers to their questions.
Hoft found a workaround in the Bacillus Calmette-Guérin (BCG) vaccine.
The most widely used vaccine in history, with more than 4 billion doses given to patients since 1921, the BCG vaccine contains a live but weakened version of the TB bacteria. The BCG vaccine is given to newborns to reduce their TB risk, but it is less effective against pulmonary TB and often wanes in effectiveness, providing little to no protection in adults.
With the BCG vaccine, Hoft saw a chance to gather data about TB in a human study without the risk of exposing participants to full strength M. Tuberculosis bacteria. To test this idea, the researchers gave 92 healthy adults the BCG vaccine, with participants receiving one of four different doses.
With participants' immune response to the BCG vaccine serving as a proxy for their exposure to a true infection, the researchers gathered much-needed data about how the immune system responds when it encounters TB.
The team applied a battery of analysis methods to samples collected from the BCG challenge sites and blood, looking for associations between BCG at the injection site, and immune responses as well as gene expression changes in blood.
The findings open up new doors for TB vaccine development.
"Our findings are important for two reasons," Hoft said. "First, this approach could enable us to screen new TB vaccines early in the pipeline and prioritize the most promising concepts, saving time and money."
"Second, we have a model to better determine what a new vaccine needs to do to protect against TB. We will be able to identify biomarkers indicating whether new vaccines could better protect someone against TB."
Among the findings that will help vaccine developers as they create new vaccines,
This last point is an intriguing finding. Doctors have long observed that men appear to be more at risk of developing an active form of TB infection, but they do not know why. In this study, researchers found differences in the immune responses of men and women to the BCG challenge, a finding that parallels doctors' observations with patients who develop the illness.
Researchers hope this new model will help advance our understanding of why men and women have different levels of general immunity.
Hoft is enthused by the study's findings, which he says could provide a road map for future TB vaccine testing.
"The BCG human challenge model is a promising approach for studying TB immunity," Hoft said. "The new data will facilitate the vaccine development process, allowing us to make progress toward our ultimate goal of eradicating TB."
Comments
Post a Comment