When Protection Improves but Uptake Craters: A Five-Year COVID-19 Warning

COVID-19 vaccination has entered an awkward phase for people with weakened immune systems. The scientific question of whether additional doses can strengthen protection is increasingly being overtaken by a behavioural one: will high-risk patients keep returning for vaccination once the emergency atmosphere has disappeared?

A five-year study from Italy shows that repeated vaccination produced far stronger antibody responses in immunocompromised patients who had initially responded poorly, yet participation in later vaccination campaigns collapsed. The result is a widening gap between what vaccination can achieve biologically and what health systems are managing to deliver in practice.

Published in Vaccines, the study, "Five-Year Effectiveness and Adherence Outcomes of SARS-CoV-2 Vaccination in Immunocompromised Patients Since the Launch of the Vaccination Campaign," was conducted by Adele Sarcone, Maria Rosaria Deodato, Alessandra De Pasquale, Caterina De Sarro, Carmelo G. A. Nobile and Claudia Pileggi of the University "Magna Græcia" of Catanzaro. The researchers followed 170 immunocompromised patients for up to five years, tracking antibody responses, infections, clinical outcomes and vaccine uptake.

What emerged was not a simple story of vaccine success or failure. It was a study of two trajectories moving in opposite directions: immune response became stronger with additional doses, while adherence weakened with each successive vaccination season.

The first two doses exposed the limits of standard vaccination

Immunocompromised patients do not begin from the same biological starting point as the general population. Organ transplantation, kidney failure, cancer and immunosuppressive treatment can all blunt the immune response, making a standard vaccination schedule less reliable for people already at greater risk of severe disease.

The Italian cohort showed just how large that gap can be. After the initial two-dose schedule, 88% of participants were classified as non-responders or low responders. Their mean anti-RBD IgG antibody level stood at 84.9 BAU/mL, indicating that the conventional early regimen generated only limited humoral immunity in most patients.

The third dose changed the pattern sharply. The share of patients remaining in the non- or low-response categories fell to 29.4%, while antibody concentrations rose significantly. After the subsequent booster, mean anti-RBD IgG levels climbed to 3447.5 BAU/mL, and 87.7% of evaluated participants were classified as high responders.

Those numbers challenge the idea that a weak initial response marks the end of the road. In this population, poor responsiveness after two doses was not fixed. Additional vaccination was associated with a substantial improvement, suggesting that immunization schedules for medically vulnerable patients may need to be built around immune status rather than simply mirror schedules used for the wider population.

The study also examined whether previous infection added a clear advantage. After the first booster, researchers found no statistically significant difference in average anti-RBD IgG levels between patients with vaccination-induced immunity and those with hybrid immunity from both vaccination and infection.

The finding shows that repeated vaccination alone was capable of generating a strong measured antibody response in patients whose early response had been weak.

Breakthrough infection was common, but severe outcomes told a different story

A second finding complicates the way vaccine performance is often discussed outside clinical settings. Many participants still contracted SARS-CoV-2 after vaccination had begun, especially during later stages of the pandemic.

At first glance, frequent infection could appear to undermine the case for continued vaccination. The clinical picture was more nuanced. Among patients who reported infection, only 11.1% experienced severe symptoms, one required intensive care, and no COVID-19-related deaths were recorded among study participants during follow-up.

This gap between infection and severe disease is central to understanding what vaccination was doing in this population. The emergence of Omicron and its sublineages increased breakthrough infections because the virus became better at evading existing immunity. Preventing every infection became a much more demanding standard than preventing hospitalization or death.

The study cannot prove that vaccination alone caused the favourable outcomes, and its antibody measurements need to be interpreted carefully. Researchers measured binding antibodies rather than functional neutralizing activity, so higher anti-RBD IgG levels cannot be treated as a direct measure of protection against every viral variant.

Immune protection is also broader than antibodies. Cellular responses may continue to provide defence against severe disease even when circulating antibody levels decline or the virus partially escapes antibody recognition. For immunocompromised patients, whose immune responses vary widely according to disease and treatment, a single laboratory marker can only tell part of the story.

The communication problem is obvious. If patients judge vaccine effectiveness mainly by whether they become infected, repeated breakthrough infections can look like evidence that boosters have stopped working. If the more important benefit is reducing the severity of disease, health systems need to explain that distinction far more clearly than they often have.

The biological gains collided with a collapse in uptake

The most dramatic result did not come from the laboratory, but from vaccination behaviour. Participation declined steadily after the primary vaccination phase. Among eligible patients, 46.5% received the 2022–2023 seasonal dose. Uptake then fell to 27.5% in 2023–2024, 11.8% in 2024–2025 and just 8.3% in 2025–2026.

The contrast with the pandemic period is severe. Adherence had been around 97% during the earlier phase, when COVID-19 dominated public attention and vaccination campaigns were intensive. Within a few years, uptake among a medically vulnerable cohort had fallen into single digits.

The reasons patients gave are revealing. Doubts about vaccine effectiveness accounted for 55% of refusals. Another 22% referred to weak recommendations or contraindications communicated by healthcare professionals. Fear of adverse effects accounted for 11.5%, while 8% believed their infection risk was low.

Those responses shift the debate away from a simplistic idea of vaccine hesitancy. A substantial part of the problem sits inside the healthcare relationship itself. Immunocompromised patients often depend on specialists to interpret risk because vaccination decisions interact with transplantation, cancer treatment, kidney disease and immunosuppressive therapies.

A hesitant or inconsistent recommendation from a clinician can carry more weight than a national campaign. The study suggests that long-term vaccine adherence may depend less on mass messaging and more on whether trusted healthcare professionals continue to make clear, confident and individualized recommendations.

The implications extend beyond COVID-19. Many preventive health programmes lose momentum once emergency funding, media attention and public urgency fade. The technical intervention may remain useful, but participation weakens because the system supporting it becomes less visible, less coordinated and less persistent.

The next problem is keeping protection alive after the crisis has passed

The study captures not just whether additional vaccination generated antibodies, but how patient behaviour evolved as COVID-19 moved from global emergency to a more routine health threat. However, its limitations prevent sweeping conclusions. The research was conducted at a single vaccination centre in Southern Italy, so the exact uptake pattern cannot automatically be applied to other countries or health systems. Fewer patients received later doses, creating the possibility of selection bias, while the cohort combined several different forms of immune impairment that may respond differently to vaccination.

Future research will need to separate those clinical groups more carefully. Transplant recipients, cancer patients and people with kidney disease may require different vaccination strategies, and larger multicentre studies could clarify which patients benefit most from additional doses and how long those benefits persist.

More detailed research on neutralizing antibodies and cellular immunity would also help connect laboratory response with actual protection. Yet the behavioural questions may now be just as urgent: why do patients disengage, why do clinician recommendations weaken, and what kinds of follow-up can sustain vaccination once the pandemic no longer feels immediate?

For lower-resource health systems, those questions are particularly important. Specialist access may be limited, adult vaccination infrastructure may be weaker, and competing health priorities can push seasonal immunization further down the agenda. A model that depends on repeated stand-alone campaigns may be difficult to sustain.

Integrating vaccination into routine transplant care, oncology, nephrology and chronic-disease services could offer a more durable approach. Instead of asking vulnerable patients to reconnect with a separate vaccination programme every season, health systems could make immunization part of the care pathways they already use.