Once an individual has received a measles jab, they are usually considered protected against measles disease for their entire life. The measles vaccine is one of the most potent vaccines in our armamentarium today. But this is not the case with most other vaccines. One needs to take several boosters for a long protection. Why is this the case?
We recently published a review of 34 currently licensed vaccines for the duration of their protective immunity, and found that only five vaccines provide long-lasting protection spanning more than 20 years and only three provide lifelong protection. Of these 34 vaccines, 15 provide 5-20 years of protection, whereas a similar number of other shots offer short-term protection that lasts around five years or less.
More importantly, barring a very few, most of the new-generation vaccines have a short duration of protection.
How do vaccines induce different immune responses?
Post-vaccination immunity develops in a complex process. In the fundamental immunological mechanism, our lymph nodes first produce the memory B cells that confer long-term protection against a disease. These cells ‘memorise’ the antigen the vaccine has delivered. In future, when a foreign object like a virus enters the body bearing the same antigen, the B cells will trigger the production of a large number of potent antibodies to destroy it, removing the infection.
These memory B cells require T cell support, and only vaccines that stimulate T cells can also induce the body to produce them.
Further, not all vaccines – including the polysaccharide typhoid and the pneumococcal vaccines – prompt the body to make B cells. In some cases, frequent boosters are required to enhance the duration of immunity the cells confer, ranging from six months to a few years. Also, vaccines trigger the production of memory B cells to different degrees, plus having memory B cells alone does not guarantee protection.
Following the administration of the measles and the rubella vaccines, the level of memory B cells in the blood plasma remains constant. It corresponds well with antibody levels decades later. This is not the case with the chickenpox, tetanus, and diphtheria vaccines – suggesting that memory B-cell persistence may not ensure antibody durability and that another mechanism may be involved in sustaining antibody levels.
Another essential immune cell, called long-lasting plasma cell (LLPC), migrates from the lymph node to the bone marrow and may endure for decades. LLPCs are the main immunological factor in vaccine-induced immunity. Every vaccine tries to create long-lasting plasma cells for lifelong protection, a.k.a. the immunology ‘holy grail’. The measles and rubella vaccines produce these cells in the bone marrow. However, some potent vaccines, such as the mRNA COVID-19 shots, fail to activate these cells in the bone marrow.
To provide long-term protection, then, vaccines must generate memory B cells and LLPCs in the bone marrow. Different vaccines differ in their ability to produce these cells, explaining the disparity in their durabilities.
What mechanism can explain the disparity?
There are three main categories of factors responsible: vaccine-related, target pathogen-related, and host-related.
Live viral vaccinations – including the vaccines for measles, rubella, yellow fever, chickenpox, and polio (oral) – provide longer lasting protection than killed pathogen or subunit vaccines. Newer platforms like ‘virus-like particle’ (VLP) also offer long-term protection. The HPV vaccines were developed using this platform.
Next, the proper interval between doses of a multi-dose vaccine, like that for hepatitis B, matters. A long interval of at least six months between the priming and the booster doses is essential for adequately processing the antigen and a robust, durable immune response. Adding adjuvants to vaccines also significantly affects vaccine-induced immune responses and their persistence. Some novel adjuvants, like TLR agonists, can directly influence memory B cell functions as well.
The durability of vaccine-induced protection also depends on the characteristics of the respective pathogens. Viruses that quickly infect the body (shorter incubation period) don’t give enough time for the immune system to respond effectively. Examples include the influenza and the SARS-CoV-2 viruses. Whether it is a natural infection or vaccine-induced, the resulting immunity is not long-standing.
The converse is also true: infections or vaccines against viruses like mumps, measles, and yellow fever, with extended incubation periods, lead to durable immunity since the immune system has more time to respond.
Further, pathogens that cause only mucosal infections but minimal blood infection, like SARS-CoV-2, influenza, and the respiratory syncytial virus, pass from one person to another in a short span, before our immune system has had the time to launch an immune response. This is the reason why reinfections are frequent with these viruses.
The genetic stability of the virus contained in a vaccine also influences the durability of immunity. We know RNA viruses are known for their high mutation rates. (Both measles and SARS-CoV-2 are single-stranded RNA viruses.) While we still use the same strain of measles vaccine isolated from the throat of David Edmonston in 1954, the SARS-CoV-2 vaccines have been updated thrice in the last four years.
This is also why the flu vaccines need to be revised twice a year. The measles virus’ surface glycoprotein is more resistant to ongoing mutations. On the other hand, only a handful of mutations at the spike protein change the antigenic nature of the SARS-CoV-2 virus.
Next, host-related factors affect durability. The individual’s age at the time of vaccination influences the persistence of vaccine-induced antibodies: the response is shorter at both extremes of age because of immaturity and senescence of the immune system, respectively. Immune responses may also vary with gender. Studies have found that biologically female bodies elicit more exuberant immune responses to infections than males. Recent studies have also found obesity may accelerate the waning of vaccine efficacy.
The time of day a vaccine is given also affects the immune response’s robustness. Shots in the morning have been demonstrated to confer better immunological responses than those later in the day. The circadian clock affects immune-cell processes like cytokine generation, cell trafficking, dendritic cell activity, and T and B cell activity. Studies in mice have found a good night’s sleep may also boost the immunological interactions and provide enduring protection.
New bioengineering technologies are evolving rapidly. With nanoparticles and virus-like particle vaccinations, antigen valence and density are finely regulated. Antigen delivery can be controlled and sustained via newer biomaterials. New adjuvants can activate specific innate immune pathways. As the mechanisms of immune response durability become more apparent, we can construct vaccines strategically to provide durable vaccine-induced protection with fewer doses.
Dr. Vipin M. Vashishtha is past convener, IAP Committee on Immunisation, and director and paediatrician, Mangla Hospital and Research Centre, Bijnor. Dr. Puneet Kumar is a clinician, Kumar Child Clinic, New Delhi, with a special interest in infectious diseases and vaccination.
