Malnutrition and humoral immunity: long-term protein deprivation. The effect of long-term protein deprivation and refeeding on delayed-type hypersensitivity (DTH) and humoral immune function was investigated in rats. Animals previously sensitized to keyhole limpet hemocyanin (KLH) were placed on a 2% protein diet ad lib for 8 weeks, after which some groups of animals were refed for up to 4 weeks. Control rats received normal rat chow. Recall skin testing with KLH, and immunization with tetanus toxoid (TT) were used to assess DTH and humoral immune responses. Weight, DTH, and antibody responses declined progressively with protein deprivation. Refeeding restored skin test responses and humoral immunity. There was a direct correlation between degree of malnutrition as reflected by weight and antibody responses as well as between DTH and antibody responses. The data demonstrate that chronic protein deprivation modulates both DTH skin testing and humoral immune responses and show that under conditions of altered immune function, there is a correlation between DTH responses and humoral immune function. Published in The Journal of surgical research (1986)

Current licensed influenza vaccines primarily protect by eliciting antibodies against the viral hemagglutinin (HA) glycoprotein, thereby blocking viral attachment and fusion with host cells. Unlike most vaccines, influenza vaccines must be administered annually because circulating viruses undergo continuous antigenic drift and population antibody titers wane over time. Despite yearly reformulation, influenza vaccine effectiveness remains highly variable, often below 45%, largely due to antigenic mismatches. These mismatches arise from ongoing HA evolution following strain selection and from egg-adaptation during production or propagation in animal cell cultures, which can alter key HA epitopes relative to circulating strains. Even when an antigenic match is favorable, repeated annual vaccination may elicit immunological phenomena that attenuate protective responses. Serial vaccination in young and older adults can increase regulatory T-cell activation, reducing vaccine-induced antibody titers. In older adults, this may be compounded by age-associated CD4+ T-cell memory populations that have reduced capacity to activate HA-specific B cells. While natural influenza infection induces durable memory B cells, conventional vaccination does not reliably generate such long-lived memory, suggesting a fundamental limitation of current vaccine platforms. Collectively, these observations underscore the need to re-evaluate influenza vaccination strategies, particularly to improve protection in high-risk groups such as older adults. Reducing antigenic mismatch remains essential and can be facilitated by improving the vaccine selection process and expanding the use of recombinant protein and mRNA vaccine production platforms that do not rely on egg- or animal-cell culture technologies. In parallel, the rational selection and development of adjuvants that minimize T-regulatory cell induction while enhancing durable memory B-cell formation and long-lived plasma cells may help overco A few plasma cells exit lymph nodes and/or spleen and migrate to the bone marrow, for long-term memory (years to decades). On leaving GC, some B cells, instead of differentiating into antibody-secreting plasma cells, differentiate into memory B cells that transiently migrate through the blood toward the extrafollicular areas of spleen and lymph nodes. These memory cells persist there as resting cells until re-exposed to their specific antigens. In essence, Tfh and Tfr cells form a balanced system in the GC, where Tfh cells provide “help” and Tfr cells provide “control, “ ensuring a high-affinity yet regulated antibody response. Created in BioRender. Gupta, R. (2026) https://BioRender.com/085abl7 . Infographic illustrating the immune response to vaccination, including antigen recognition, B cell activation, clonal proliferation, plasma and memory B cell formation, and the role of boosters in rapid antibody production and long-term immunity. Over time, antibody levels decline, sometimes falling below the estimated protective levels, likely due to a reduction in memory B cells and plasma cells. The protective levels of circulating antibodies are unknown for most diseases. Despite low circulating antibody levels for extended periods, most vaccines provide long-term or lifelong protection without the need for booster doses, except for toxin-mediated diseases such as tetanus and diphtheria. Protection against most diseases is not necessarily achieved by maintaining high circulating antibody levels. Emerging evidence from immunization models further indicates that the magnitude and timing of the Tfr response critically shape vaccine-induced humoral immunity, such that early or excessive engagement, such as repeated immunization of this regulatory axis, can dampen GC responses and reduce the magnitude and durability of antibody production ( 79 – 81 ). Collectively, these findings provide a mechanistic framework supporting the concept of vaccine “blunting, “ or “attenuated magnitude”, wherein heightened Tfr activity attenuates the breadth, magnitude, and persistence of antigen-specific antibody responses. As discussed in section 4.5, repeated annual vaccination generates Tregs, specifically Tfr cells, in all age groups ( 39 , 82 ) and CD4+ memory T cells in the elderly, which can diminish protective antibody responses ( 40 ). These cells can suppress the immune system’s ability to fight off influenza infections, affecting both humoral and cellular responses, including the failure to elicit memory B cells, which are primarily responsible for the long-term protection provided by vaccines. Moritzky et al. ( 83 ) observed a negative association between preexisting HA-specific antibodies and postvaccination antibody levels. There are numerous scientific reports on the reduction in influenza vaccine effectiveness after repeated vaccinations ( 49 , 120 – 122 , 129 – 159 ), starting with a 1970s vaccine trial in an English boarding school, which observed that infection rates were higher among boys vaccinated in the current and previous seasons than among those receiving their first vaccination ( 160 ). These observations from three outbreaks of influenza A in a school suggested that annual revaccination with inactivated influenza A vaccine confers no long-term advantage ( 160 ). During the 2009 pandemic, it was noted that older people had lower rates of infection than the younger population due to historical cross-immunity to conserved antigens from prior H1N1 viral infections (which were common in the late 1970s); thus, their original antigenic exposure offered protection ( 63 – 65 ). Based on these observations, it may be inferred that immune memory to influenza infections is long-term, and that repeated vaccinations are not beneficial in protecting against emerging strains. New vaccines comprising HA from potential circulating strains should be developed using recombinant protein expression systems and mRNA vaccine technology