Subject: Vaccines

Why in the News

A study gave two doses of the Bacillus Calmette Guerin vaccine a month apart to 23 older adults and tracked blood and cerebrospinal fluid for a year, finding monocytes switching on genes for a faster immune response. This is evidence of trained immunity operating within the central nervous system. The tension is between a cheap, decades old vaccine with a large safety record and a study too small to establish clinical benefit.

Note: Bacillus Calmette-Guérin (BCG) vaccine is more than 100 years old. It was first given to a human on July 18, 1921. Two French scientists, Albert Calmette and Camille Guérin, made the vaccine to stop tuberculosis (TB).

What is trained immunity?

1. About: Trained immunity is the capacity of innate immune cells to mount a stronger response to a later, unrelated challenge after an initial exposure, through lasting changes in gene expression.
2. How it differs from adaptive immunity: Adaptive immunity is pathogen specific and mediated by lymphocytes. Trained immunity is non specific and mediated by innate cells such as monocytes.
3. Mechanism: The change operates through epigenetic and metabolic reprogramming rather than through antibody memory.
4. Why BCG: BCG is the best documented inducer of trained immunity, which is why it is used to test the effect.

What did the study actually find?

1. Sample and design: 23 older adults were enrolled, roughly half with cerebrospinal fluid biomarkers of Alzheimer’s disease, given two BCG doses a month apart.
2. Immune change: Monocytes switched on genes associated with a faster immune response.
3. Functional test: Monocytes responded more strongly to lipopolysaccharide, a standard bacterial stimulus, confirming a functional and not merely transcriptional change.
4. Amyloid movement: Amyloid fell in cerebrospinal fluid and rose in blood among participants without established Alzheimer’s, and not among those with it.
5. Location of the effect: The change was detected in the central nervous system compartment, which is the finding’s principal claim.

What are the study’s stated limits?

1. Sample size: 23 participants is too small to detect a clinical effect.
2. No control arm: The study had no placebo group, so observed changes cannot be separated from natural variation.
3. No cognitive change: Cognitive scores were unchanged over the year.
4. Directional ambiguity: Amyloid shifting from cerebrospinal fluid to blood is consistent with clearance and is not proof of clearance.

Why does a cheap vaccine matter for this disease?

1. Cost comparison: BCG is inexpensive and carries decades of safety data, against anti amyloid drugs that are expensive and require infusion infrastructure.
2. Existing supply: BCG is already manufactured at scale for tuberculosis immunisation.
3. Repurposing precedent: A five year BCG cohort in type 1 diabetes established the model of testing the vaccine for a non tuberculosis indication.
4. Underlying hypothesis: Chronic low grade inflammation with ageing, described as inflammaging, is implicated in neurodegeneration, and trained immunity is one route to modulating it.

Challenges in translating this finding

1. Blood brain barrier access: Demonstrating that a peripheral vaccine changes central nervous system immunity requires invasive sampling. e.g. the cerebrospinal fluid collection this study depended on.
2. Amyloid hypothesis contestation: Amyloid reduction has not reliably produced cognitive benefit. e.g. the modest clinical effect sizes reported for approved anti amyloid antibodies.
3. Trial duration: Neurodegeneration progresses over years, so trials must run long. e.g. the five year design of the BCG type 1 diabetes cohort.
4. Vaccine supply competition: Diverting BCG to a new indication competes with tuberculosis immunisation demand. e.g. periodic global BCG supply shortages affecting national immunisation programmes.
5. Strain variability: BCG substrains differ in immunological potency, complicating replication. e.g. the differing efficacy estimates across BCG trials attributed to substrain variation.
6. Diagnostic access: Identifying preclinical Alzheimer’s requires biomarker testing unavailable at scale in India. e.g. limited availability of cerebrospinal fluid and amyloid imaging assays outside tertiary centres.

Conclusion

The study’s contribution is the demonstration that trained immunity can be detected within the central nervous system, which extends a peripheral immunology concept into neurology. It establishes a mechanism, not a treatment, since 23 participants without a control arm and with unchanged cognition cannot support a clinical claim. The next milestone is a randomised controlled trial with a placebo arm and cognitive endpoints over a multi year horizon.

Back2Basics: Bacillus Calmette Guerin vaccine

1. A live attenuated vaccine derived from Mycobacterium bovis, first administered in humans in 1921.
2. Used primarily against severe childhood forms of tuberculosis, including tuberculous meningitis and miliary tuberculosis.
3. Included in India’s Universal Immunisation Programme, given at birth or as early as possible thereafter.
4. Provides limited protection against pulmonary tuberculosis in adults, which is why a new tuberculosis vaccine remains a research priority.
5. Also used as an intravesical immunotherapy for non muscle invasive bladder cancer.
6. Manufactured in India at the BCG Vaccine Laboratory, Chennai, among other facilities.

Government Initiatives

1. National Tuberculosis Elimination Programme: Targets tuberculosis elimination, covering diagnosis, treatment and nutritional support for patients.
2. Ni-kshay Poshan Yojana: Provides direct benefit transfer for nutritional support to tuberculosis patients on treatment.
3. Universal Immunisation Programme: Provides BCG and other vaccines free of cost, targeting infants and pregnant women.
4. National Programme for Health Care of the Elderly: Provides dedicated geriatric health services including cognitive and mental health care.
5. Indian Council of Medical Research clinical trial network: Supports multicentre trials, including for tuberculosis vaccine candidates.

Way Forward

1. Run a controlled trial: Replicate the finding with a placebo arm and a sample large enough to detect a cognitive effect.
2. Standardise the substrain: Fix the BCG substrain across trial sites so results are comparable.
3. Protect immunisation supply: Ensure any repurposing trial does not draw on doses allocated to childhood tuberculosis immunisation.
4. Expand biomarker capacity: Build cerebrospinal fluid and blood biomarker testing capacity so preclinical cases can be identified for trial enrolment.
5. Fund domestic replication: Support an Indian cohort, since India carries both the largest BCG immunised population and a rapidly ageing one.

“[2022, GS3, 15 marks] What is the basic principle behind vaccine development? How do vaccines work? What approaches were adopted by the Indian vaccine manufacturers to produce COVID-19 vaccines?”