The COVID-19 pandemic has been a roller-coaster for vaccinology — from a rare show of truly global collaboration between governments, multilateral agencies, the scientific community, and industry to huge public demand for rapid vaccine development against the new virus that had brought the world to its knees to sudden concerns of “too rapid” development when many vaccines could be developed in record time. Some wanted “booster doses”, and others worried about “too many doses”.
So when the U.S. Food and Drug Administration announced in September 2021 that the third doses of the Pfizer and the Moderna COVID-19 vaccines would soon be available to Americans who were first in line to receive their initial two-shot vaccines, some experts questioned the need for it for most people — except the elderly or immunocompromised — and called it “over-vaccination” owing to a lack of data.
Later, the third dose became the norm worldwide, although India still called it a “precaution dose” and continues to do so, while many Western countries recommend repeated boosters, some with updated vaccines against the current Omicron variant. The debate over the best vaccination strategy continues.
The man who received 217 shots
In January 2022, an octogenarian from Madhepura district in Bihar claimed to have received more than 11 doses of the COVID-19 vaccine because it helped him with joint and back pain that had eluded other forms of treatment. At the time, some scientists worried about “over-vaccination”. Since the subsequent doses beyond the first two may not have been reported, it faded from the headlines.
But on March 4, a study published in The Lancet reported a shocking case of “over-vaccination” by a 62-year-old German man who received over 217 COVID-19 shots over 29 months for “private reasons”.
Researchers found out about his case from media reports and conducted a detailed study to investigate the immunological and other effects of over-vaccination on his body. Their investigation revealed much about immune function and the effects of over-vaccination. They compared their findings to a reference cohort of 29 healthy persons who received ‘only’ three COVID-19 vaccine doses.
Between November 2019 and October 2023, the researchers conducted routine examinations for various reasons, which indicated no vaccination-related anomalies on 62 parameters. No vaccine dose caused issues for the German individual. He never got a minor SARS-CoV2 infection either, according to rapid antigen/RT-PCR and nucleocapsid serology assays.
The antibody titsre were much greater than the control group vaccinees, with serum neutralisation capability 5.4-fold and 11.5-fold higher for wild-type and Omicron B.1.1.529 spike proteins, respectively.
They also reported that he exhibited antibodies that were not found in the control group and that some antibodies were also detected in his saliva. Advanced “quality” tests of antibodies showed no significant difference from the control group. Strong “over-vaccination” did not increase or impair antibody quality either.
Finally, the researchers evaluated individual immune cells to discern the “exhaustion” of immune cells from repeated vaccination — and found none. Throughout the study, more antibody titres showed the individual’s immune system’s ability to respond to the antigen despite hyper-stimulation.
In sum, even after over-vaccination, the COVID-19 vaccinations were well-tolerated and effective.
Are too many vaccine doses bad for you?
The investigations did not harm the person, and raised many questions: Are too many random vaccine doses at random intervals safe for anyone? Can a single case study generalise safety? Do two to three years suffice to assess vaccine safety? How might such high vaccine doses affect an individual’s immune system?
Many experts have discussed ‘immune tolerance’ and ‘immune exhaustion’ — especially of the T cells. Long COVID pathogenesis, when the SARS-CoV-2 virus persists in the body for a long time, has been carefully investigated in relation to this issue. Scientists have found no evidence that COVID-19 vaccinations do this. The vaccines merely briefly expose the immune system to antigens. Each shot injects a small quantity of antigen, triggering a momentary immunological response.
However, naturally sick people produce viruses and antibodies throughout the body for days or weeks. The human common-cold coronavirus and rhinoviruses infect people multiple times every year, often at short intervals, without harming their immune systems. Our immune system responds to environmental exposure on an hourly basis without getting tired. The recent vaccines are more sophisticated. They use only a portion of an organism or a few antigens, unlike smallpox and whole-cell pertussis vaccines, which include thousands.
In the new study, immunological profiling indicated repeated vaccinations or infections stimulated the immune system, making it more responsive. Interestingly, the immune system also developed faster, stronger, and broader, protecting against more new variants.
A probable downside
Cancer and HIV can cause immune-fatigue due to chronic foreign-object exposure. So the immune system might become ‘exhausted’ and stop responding after repeated encounters. Thankfully, COVID-19 has not shown this yet. Recent research has revealed that repeated vaccines and spontaneous infections in fact boost COVID-19 immunity.
Despite these promising results, over-vaccination should be avoided. The COVID-19 vaccines have been associated with autoimmune diseases like immune thrombotic thrombocytopaenia, autoimmune liver disorders, Guillain-Barré syndrome, IgA nephropathy, rheumatoid arthritis, and systemic lupus erythematosus.
Molecular mimicry, autoantibody synthesis, and vaccine adjuvants appear to contribute significantly to these disorders. The relationship between a COVID-19 shot and these conditions’ symptoms is unclear.
This said, overloading the immune system rarely causes harm. Hypervaccination may rarely cause an ‘Arthus reaction’, a condition characterised by localised acute small-vessel inflammation and possibly entire limb edema. Repeated tetanus and diphtheria vaccination injections have been shown to have this reaction.
As we know, there are two broad types of immunity: innate and adaptive. When innate immunity is permanently stimulated, and the intensity of the reactions is stronger, these mechanisms may be directed against the host and subsequently stimulate acquired immunity. The cytokines, oxidative stress, and high nitric oxide production accompany this manifestation.
Other issues pertain to the principles of immunisation. In this instance, an interval between doses ranged from two days to two months. Most vaccines, including the mRNA vaccines, work best when there is a defined minimum interval between the two doses against one particular disease. A shorter interval usually elicits a suboptimal immune response than adequately spaced doses.
One must stick to the laws of science and, in this case, the principles of vaccination. We must endorse the caution the authors advised to avoid attempting such over-vaccination without evidence on a sufficient number of subjects. In addition, the study is a good illustration of how we can seize on the opportunities to advance science for the benefit of all. Conversely, the results will also reassure the vaccine-hesitant community about the safety of vaccines.
Dr. Puneet Kumar is a clinician, Kumar Child Clinic, New Delhi, with a special interest in infectious diseases and vaccination. Dr. Vipin M. Vashishtha, is past convener, IAP Committee on Immunisation, and director and pediatrician, Mangla Hospital and Research Center, Bijnor.
