Evaluarea răspunsului imun postvaccinal anti-HPV la populația generală cu şi fără antecedente de infecție virală – review al literaturii

1. Introduction and background

Human papillomavirus (HPV) infection represents one of the most widespread sexually transmitted infections worldwide, affecting over 80% of sexually active individuals throughout their lifetime⁽²⁹⁾. Among the more than 200 identified genotypes, approximately 14 are considered high-risk oncogenic types, responsible for over 99% of cervical cancers, as well as a significant proportion of anogenital and oropharyngeal cancers⁽²⁹⁾.

Prophylactic vaccines based on virus-like particles (VLPs) of the L1 capsid protein – bivalent (2vHPV), quadrivalent (4vHPV) and nonavalent (9vHPV) – have demonstrated high efficacy in preventing persistent infections and precursor lesions^(3,27). These vaccines induce a strong humoral immune response with antibody titers several orders of magnitude higher than those generated by the natural infection⁽²²⁾.

A particularly relevant question for public health programs is whether individuals with prior HPV exposure – either serological evidence or ongoing infection – exhibit a comparable immune response to those who were never infected. Studies suggest that previously infected individuals may develop a secondary (anamnestic) immune response with enhanced antibody maturation, though the clinical efficacy tends to be slightly lower than in immunologically naive cohorts^(2,6).

The aim of this narrative review is to synthesize the available data on the post-vaccination immune response to HPV in the general population, comparing subgroups with and without a history of HPV infection, and to discuss the clinical and public health implications of these findings.

2. Immunological basis of HPV vaccination

HPV vaccines work by inducing a robust humoral immune response against the L1 capsid protein, which is presented as a virus-like particle (VLP). These VLPs are non-infectious but closely mimic the antigenic structure of the native virion, eliciting a strong B-cell-mediated immune reaction⁽³¹⁾.

In the study conducted by Scherer et al. (2014)⁽⁸⁾, vaccination was shown to generate memory B cells capable of producing high-avidity neutralizing antibodies upon reexposure, ensuring long-term protection. In a later analysis, Scherer et al. (2016)⁽⁹⁾ observed that even a single vaccine dose could induce functional B-cell memory, which can be effectively reactivated by subsequent antigen exposure.

Unlike natural infection, which generates low and variable antibody titers, vaccination produces antibody levels 10-100 times higher, with significantly greater avidity⁽¹⁰⁾. Tsang et al. (2022)⁽³²⁾ demonstrated that vaccine-induced antibody avidity remains markedly higher than that from natural infection and remains stable over time.

The cellular immune response (T-helper and cytotoxic T cells) also contributes to the maintenance and regulation of antibody production, although the main protective mechanism remains humoral immunity⁽¹²⁾.

3. Post-vaccination immune response in individuals without prior HPV infection

Most pivotal clinical trials (PATRICIA, FUTURE I/II, CVT) primarily included seronegative and HPV DNA-negative individuals at baseline. These cohorts showed seroconversion rates exceeding 98% one month after completing the full vaccination schedule^(4,5).

In the PATRICIA trial⁽⁴⁾, it was demonstrated that immunologically naive women developed neutralizing antibody titers more than 100 times higher than those observed after natural infection, maintaining protective levels for at least 9.4 years. Similarly, the Costa Rica Vaccine Trial (CVT), analyzed by Kreimer et al. (2018)⁽⁶⁾, found that anti-HPV 16/18 antibodies persisted for up to 16 years following a single vaccine dose, with no evidence of waning protection.

Furthermore, younger adolescents (9-14 years old) have been shown to mount significantly stronger immune responses compared with adult women, supporting the recommendation to vaccinate prior to sexual debut^(14,28).

4. Post-vaccination immune response in individuals with a history of HPV infection

4.1. Seropositive but DNA-negative individuals

Several studies have demonstrated that individuals with prior HPV exposure (seropositive but without active infection) develop immune responses comparable to (or even higher) those of naive individuals. In the study by Mac Eochagain et al.^(2,23), vaccination of seropositive, DNA-negative women produced a clear “booster” effect, significantly increasing neutralizing antibody titers.

For example, in the FUTURE II study, women with baseline seropositivity for HPV 16/18 experienced accelerated antibody titer increases after vaccination, indicating the reactivation of immune memory⁽³³⁾.

4.2. DNA-positive individuals (active infection)

In contrast, among individuals with active infection at the time of vaccination, the clinical benefit is reduced. Although seroconversion occurs, vaccination does not treat the existing infection, but rather prevents new infections with vaccine-included types^(3,5).

A meta-analysis by Lin et al. (2019)⁽³⁴⁾ demonstrated that vaccine efficacy in previously infected women is significantly lower compared with unexposed cohorts, although there remains a measurable benefit in preventing reinfection with other types.

5. Durability and quality of the post-vaccination immune response

The durability of the immune response is a key determinant of long-term vaccine effectiveness. Long-term follow-up studies have shown that neutralizing antibodies remain at protective levels for over a decade after vaccination, even with reduced-dose regimens.

In the 14-year follow-up study conducted by Kjaer et al. (2020)⁽¹⁾ among participants vaccinated with the quadrivalent vaccine (4vHPV), anti-HPV 6/11/16/18 antibodies persisted, and no new infections with these types were detected. Similar findings were reported in the 16-year analysis of the Costa Rica Vaccine Trial (CVT) by Porras et al. (2024)⁽⁷⁾, which demonstrated that anti-HPV 16/18 titers remained several-fold higher than those induced by natural infection, even after a single vaccine dose.

Tsang et al. (2022)⁽³²⁾ demonstrated that antibody avidity continues to increase over time, reflecting ongoing immune maturation. In a study by Miller et al. (2021)⁽¹⁷⁾, the evaluation of antibody avidity and T-cell responses showed consolidation of both humoral and cellular immunity after vaccination, with robust responses persisting even 10 years post-immunization.

By comparison, natural HPV infection induces weaker and shorter-lived antibody responses. Scherpenisse et al. (2013)⁽¹⁰⁾ demonstrated that infection-induced antibodies show lower avidity and are less stable over time compared with vaccine-induced antibodies.

Collectively, these findings indicate that vaccine-induced immunity is long-lasting, high-quality and sufficient to provide durable protection without the need for booster doses in the general population.

6. Factors influencing the post-vaccination immune response

The immunologic effectiveness of HPV vaccines can be influenced by several biological and individual factors.

6.1. Age at vaccination

Age is one of the most significant determinants of immune response. Multiple studies have shown that adolescents aged 9-14 mount significantly stronger immune responses than young adults^(14,29). In the study by Apter et al. (2015)⁽³⁵⁾, a two-dose schedule in girls aged 9-14 years old was demonstrated to be immunologically noninferior to a three-dose schedule in adult women.

6.2. Vaccine type and adjuvants

The composition of the vaccine adjuvant directly influences the magnitude and durability of the immune response. The bivalent vaccine (2vHPV, AS04 adjuvant – aluminum hydroxide plus monophosphoryl lipid A) produces significantly higher titers for HPV 16/18 and provides some cross-protection against phylogenetically related types (HPV 31, 33 and 45)⁽³⁾. By contrast, the quadrivalent (4vHPV) and nonavalent (9vHPV) vaccines provide broader coverage with comparable titers⁽⁵⁾.

6.3. Immune status and comorbidities

Immunocompromised individuals (e.g., HIV-positive) often display a lower antibody response and, therefore, require the full three-dose regimen. However, even in these populations, vaccination induces measurable seroconversion and functional antibodies⁽¹⁵⁾.

6.4. Sex and genetic factors

Minor sex-based differences have been observed in antibody titers – with women showing slightly higher values than men –, but the clinical efficacy remains equivalent⁽¹⁶⁾.

7. Clinical and public health implications

Current immunological evidence strongly supports the importance of HPV vaccination for all target populations, regardless of previous infection history. The World Health Organization⁽²⁹⁾ and the Centers for Disease Control and Prevention⁽²⁸⁾ recommend vaccination for both girls and boys aged 9-14 years old, ideally before sexual debut when immune responsiveness is maximal.

In the study by Mac Eochagain et al. (2022)⁽²⁾, the vaccination of previously seropositive but DNA-negative wo­men was associated with an approximately 87% reduction in the risk of persistent reinfection with HPV 16 and 18. Conversely, for DNA-positive individuals, vaccination had limited clinical effect, serving mainly to prevent future infections rather than treating existing lesions⁽⁵⁾.

These findings reinforce that HPV vaccination is prophylactic, not therapeutic, although it can strengthen preexisting natural immunity.

From a public health perspective, simplified regimens such as the single-dose schedule, validated in the DoRIS and KEN SHE trials^(18,19), could greatly improve vaccine coverage in resource-limited settings without compromising immunogenicity.

Population-level studies have shown that widespread vaccination correlates with substantial reductions in HPV prevalence and precancerous cervical lesions^(1,29), highlighting its major contribution to cervical cancer prevention.

8. Conclusions

HPV vaccines elicit a strong, durable immune response characterized by high titers of neutralizing antibodies and superior avidity compared with natural infection. Individuals without prior HPV exposure achieve the strongest immune responses and the highest clinical efficacy; however, previously exposed individuals still benefit through a pronounced “booster” effect of immune memory.

The post-vaccination immune response remains stable for over 10-15 years, supporting the absence of a need for routine booster doses in the general population.

Differences observed across vaccine types, dosing regimens and host factors (age, sex, immune status) provide valuable insight into the adaptability and robustness of HPV vaccine platforms, justifying global expansion of immunization programs.

In summary, current immunological evidence clearly demonstrates that HPV vaccination remains the most effective primary prevention strategy against cervical and other HPV-related cancers, providing strong protection in both HPV-naive and previously infected individuals through durable, high-quality immune responses.

Autor corespondent: Octavian Munteanu E-mail: octav_munteanu@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.