BMC Women's Health Publishes a Deeply Flawed Study on Parental Acceptance of HPV Vaccinations. Plus: Three Key Questions Required of Any HPV Vaccine Efficacy Trial

Two especially fatal aspects: Their definition of "knowledge" levels, and their own disregard of the flaws in the definition of efficacy of HPV vaccine studies.

Re: “Global parental acceptance, attitudes, and knowledge regarding human papillomavirus vaccinations for their children: a systematic literature review and meta-analysis” BMC Women's Health

HPV vaccines, such as the bivalent, quadrivalent, and nonavalent vaccines, target up to 9 high-risk HPV types associated with cancer. The nonavalent vaccine (Gardasil 9) covers the following types: HPV 16, 18, 31, 33, 45, 52, and 58 (high-risk for cancer) as well as HPV 6 and 11 (low-risk but responsible for genital warts).

However, there are at least 5 other high-risk HPV types (such as HPV 35, 39, 51, 56, and 59) that are not covered by the current vaccines but are known to be associated with a risk of cancer development, particularly cervical cancer. Additionally, some less frequent types like HPV 66 and HPV 68 are occasionally implicated in cancers but are also not targeted by vaccines. Past studies showing type replacement are ignored in more recent studies on efficacy.

Heyde et al.'s recent publication on global parental acceptance, attitudes, and knowledge regarding HPV vaccination raises several significant methodological and interpretational concerns that warrant serious attention. While the systematic review and meta-analysis aim to provide insight into the global acceptance of the HPV vaccine, they fail to address adequately several critical issues that fundamentally undermine their conclusions. A more rigorous examination of these flaws is essential for ensuring the reliability of findings and guiding public health policies appropriately.

Sample Size and Bias

A key concern lies in the small and potentially non-representative sample size used in the study, which severely limits the generalizability of its findings. The study introduces considerable bias without accounting for regional differences in vaccine access, local health policies, or cultural attitudes toward vaccination. The limited diversity in participant selection restricts the ability to apply these findings to broader, more diverse populations. It is crucial to ensure that this study is designed with adequate sample sizes and participant diversity to reflect the true variability in parental attitudes and vaccine acceptance.

Confounding Factors

Equally concerning is the study’s failure to control for confounding factors such as socioeconomic status, healthcare access, and local health education programs. These factors can significantly influence knowledge, attitudes, and acceptance of vaccines, and without properly accounting for them, the study risks misattributing attitudes to incorrect factors. The lack of control for such variables critically undermines the validity of the study, making its conclusions questionable at best.

Methodological and Analytical Shortcomings

The study’s methodology also requires closer scrutiny. Issues such as the design of survey questions, data collection processes, and analytical techniques can introduce bias and inconsistency if not rigorously calibrated. Methodological flaws in these areas can lead to skewed results and incorrect conclusions. Future studies must employ well-validated methodologies and receive comprehensive peer review to ensure the reliability of their conclusions.

Statistical Power and Significance

Due to the small sample size, the study likely suffers from low statistical power, making it less capable of detecting true effects. Moreover, the improper use of inferential statistics raises the risk that observed effects may have occurred by chance. This diminishes the reliability of the findings and calls into question the robustness of the conclusions. Statistical rigor is essential when analyzing public health data, particularly when shaping policies that affect broad populations.

Publication Bias

Additionally, publication bias must be considered. It is well-documented that positive or expected results are more likely to be published, which can skew perceptions of consensus on issues like HPV vaccination acceptance. The failure to report null or negative results may give an overly optimistic view of vaccine acceptance, distorting the reality of public attitudes and preventing a balanced understanding of the issue.

Related to this issue is the fact that the authors are apparently unaware that HPV vaccination does not reduce the incidence of diagnosis of cervical cancer.

HPV Type Replacement and Its Public Health Implications

Beyond the methodological concerns of the study, a more pressing issue relates to the growing body of evidence documenting HPV type replacement following vaccination. While the study under review does not address this phenomenon, it is critical to recognize the implications for public health.

First, most, if not all, studies reporting HPV vaccine efficacy examined vaccine-targeted HPV type-related neoplasms. Estimates of the efficacy of the vaccine at preventing HPV-related neoplasms of any kind and of cervical cancer itself are woefully overestimated.

HPV type replacement refers to the replacement of vaccine-targeted HPV types with non-vaccine types, some of which may pose a higher oncogenic risk. Multiple studies have documented this phenomenon:

• A CDC study examining HPV prevalence among sexually active females aged 14 to 24 demonstrated no net change in overall HPV infection rates following the introduction of the vaccine. This suggests that while the vaccine may reduce specific targeted types (such as HPV-16 and 18), other high-risk non-vaccine types are emerging, likely due to type replacement.

• Research conducted by Fisher et al. (2016) in Germany confirmed the replacement of vaccine-targeted HPV types with high-risk non-vaccine types, raising concerns about the long-term efficacy of current vaccination programs. The study specifically found that HPV types once considered low-risk have now been reclassified as high-risk, underscoring the danger of relying on vaccines that only target a limited number of HPV strains.

• A study by Guo et al. (2015) compared vaccinated and unvaccinated women aged 20 to 26 and found that vaccinated women had a significantly higher prevalence of high-risk non-vaccine HPV types. This finding points to the real possibility that the vaccine, while effective against certain strains, leaves individuals vulnerable to other more dangerous strains.

• The Mollers et al. (2013) study from the Netherlands highlighted the possibility of type replacement as a significant concern, emphasizing the need for continued surveillance and research to assess the long-term effects of HPV vaccination on non-vaccine HPV types.

(See Dr. Lyons-Weiler’s slides for these references and more)

These studies indicate a real and growing concern that partial vaccination against HPV may inadvertently result in an increased risk of infection by non-vaccine types, potentially leading to higher rates of HPV-related cancers in the long term.

This risk is further supported by data from the UK, which shows rising cervical cancer rates in vaccinated populations, particularly among women in their twenties. Such trends suggest that current vaccines may not offer the comprehensive protection against HPV-related cancers that they were designed to provide, and they reinforce the need for ongoing surveillance and research into the phenomenon of type replacement.

The study on global parental acceptance of HPV vaccination contains numerous methodological flaws that undermine its conclusions. The small sample size, lack of control for confounding factors, and questionable statistical power all point to serious issues with the reliability of the findings. Furthermore, the failure to address the growing evidence for HPV type replacement—a documented phenomenon that raises concerns about the long-term efficacy and potential dangers of the vaccine—calls into question the adequacy of current HPV vaccination programs.

As cervical cancer rates rise among vaccinated cohorts, particularly in the UK, public health policies must be based on comprehensive, reliable evidence. Future research must rigorously address these concerns to ensure that HPV control programs achieve their intended public health outcomes without unintended negative consequences. This includes encouraging early abstinence, Pap smears for sexually active young women, and encouraging safe sex with limited partners. Pap smears can be a curative diagnostic for early neoplasms that can become frank cervical cancer.

Three Key Questions on Recent Studies Reporting HPV Vaccine Efficacy Reveal Common Flaws

There are three key questions that any study of HPV vaccine claiming efficacy against cervical cancer must answer.

1. Does the study mention type replacement?

2. Does the study report % of cancers associated with less frequent, non-vaccine-targeted and increasing % types?

3. Was the follow-up period in the study sufficiently long to detect type replacement and increase in cancers associated with non-vaccine targeted HPV types?

Recent studies (2019-present) also tend to share common flaws in their handling of critical aspects related to HPV vaccination outcomes. First, they often fail to adequately address type replacement, with most studies providing limited or no discussion on how non-vaccine-targeted HPV types might rise in prevalence following vaccination efforts. Second, the studies tend to omit detailed percentage distributions of cancers caused by these less frequent HPV types, instead focusing on overall vaccine efficacy and the suppression of high-risk strains like HPV16 and 18. This lack of specificity leaves a significant gap in understanding the full spectrum of HPV-related cancer risks. Additionally, there is often insufficient long-term follow-up to track the evolution of cancer incidence attributable to non-vaccine HPV types, leaving the longer-term consequences of vaccination programs unclear. These omissions hinder a complete evaluation of the vaccines' broader epidemiological impacts.

I chose four studies that reported on efficacy published since 2019 or later:

First Study: PLOS Medicine 2020 on Advances in Cervical Cancer Prevention

This study does not adequately address type replacement and its implications. While it mentions non-vaccine-targeted types in passing, such as HPV33 and HPV52 accounting for a small number of invasive cervical cancer cases, it fails to alert that they may rise in prevalence due to the vaccine reducing other types. They did not provide the percentage distribution of these types over time, leaving gaps in understanding whether these types are on the rise due to vaccine-targeted type suppression. The lack of long-term follow-up also limits its usefulness in evaluating whether non-vaccine-targeted types are becoming more prevalent over time. Furthermore, the study focuses primarily on elimination goals - an impossibility with non-vaccine targeted types on the rise. There are at last count without critically assessing emerging shifts in HPV type dynamics, which weakens its applicability in broader public health planning.

Second Study: Human Papillomavirus Vaccine Efficacy and Effectiveness against Cancer

The study "Human Papillomavirus Vaccine Efficacy and Effectiveness against Cancer" (Kamolratanakul & Pitisuttithum, 2021) does not comprehensively address all three key questions. The study does not explicitly mention type replacement, a crucial factor in understanding whether non-vaccine HPV types might increase due to the suppression of vaccine-targeted types. This omission leaves a significant gap in assessing the long-term dynamics of HPV prevalence, as type replacement could affect the overall effectiveness of vaccination programs. The study also does not provide a detailed breakdown of the percentage of cancers caused by less frequent, non-vaccine-targeted HPV types. While it discusses the effectiveness of the nonavalent vaccine against nine types (including HPV 31, 33, 45, 52, and 58), it fails to explore how these or other less common types might be contributing to cancer incidence, further limiting its scope.

Finally, the study emphasizes the vaccine's strong efficacy against targeted HPV types and highlights the need for global cooperation to improve vaccine accessibility, particularly in low- and middle-income countries. However, it falls short in discussing long-term ecological effects, such as the potential for type replacement or shifts in non-vaccine types, which are essential for understanding real-world vaccine outcomes. Lastly, although the follow-up period is substantial (up to 10 years in some cohorts), it may not be sufficient to assess the full impact of vaccination on long-term cancer prevention or type replacement, given the long latency period between HPV infection and cancer development. This limitation hampers the study’s ability to fully evaluate the vaccine's long-term efficacy and impact on non-vaccine-targeted types.

Third Study: HPV Vaccination and the Risk of Invasive Cervical Cancer | New England Journal of Medicine

The study by Lei et al. does not provide detailed data or discussion on cervical cancer rates from non-vaccine HPV types in the primary analysis. The focus of the study is on the efficacy of the quadrivalent HPV vaccine, which targets HPV types 6, 11, 16, and 18. The data primarily reflect the reduction of cervical cancer linked to vaccine-targeted types, specifically HPV types 16 and 18, which are the main oncogenic types responsible for the majority of cervical cancer cases.

The mention of "84.4% of invasive cervical cancers diagnosed in persons 30 years of age or younger were associated with HPV types 16 or 18" suggests a high efficacy of the vaccine against these types but does not thoroughly explore or quantify the role of non-vaccine HPV types in the development of cervical cancer. There is no detailed presentation of cancer cases caused by other high-risk HPV types (e.g., HPV types 31, 33, 45, 52, 58, etc.), which are not covered by the quadrivalent vaccine.

This omission is significant because the potential rise in non-vaccine types due to type replacement is not discussed in the results. The study acknowledges the dominance of types 16 and 18 in cervical cancer cases but does not explicitly track or account for the impact of other high-risk HPV types that could lead to cervical cancer in the vaccinated population.

Thus, the study's focus on vaccine-targeted types and lack of comprehensive data on other HPV types may lead to an overestimation of the vaccine's overall efficacy in preventing all forms of cervical cancer, particularly those caused by non-vaccine HPV types.

Fourth Study: Human papillomavirus vaccine efficacy against invasive, HPV-positive cancers: population-based follow-up of a cluster-randomised trial. BMJ Open

The study does not explicitly address type replacement. It focuses primarily on vaccine-targeted types (HPV16, HPV18, etc.), and while cross-protection against other types (such as HPV33, HPV45, and HPV52) is mentioned, there is no detailed exploration of the possibility that the suppression of vaccine-targeted types could lead to the emergence of non-vaccine-targeted types. This is a critical oversight, as type replacement could affect the long-term efficacy of vaccination.

The study leaves an important gap in understanding the prevalence and potential rise of non-vaccine-targeted HPV types over time.

Given the latency between HPV infection and cancer development, even longer follow-up periods might be necessary to capture the full picture, particularly regarding type replacement and non-vaccine-targeted HPV types. Longer-term monitoring would help solidify conclusions about the vaccine’s comprehensive impact.

We need greater perspicuity toward a full understanding of the effects of HPV vaccines on human health. Authors are urged caution in interpreting past results on HPV vaccine efficacy; since they are based on rates of reduction of HPV vaccine-targeted types and ignore type replacement, there are missing data. This emphasizes the need for more thorough research on HPV type replacement and its implications for vaccine efficacy. Public health policies can only be effectively designed to protect populations' well-being worldwide through careful, scientifically sound investigations.

See "High-Risk HPV Type Replacement Follows HPV Vaccination" Children's Health Defense

Download Dr. Lyons-Weiler’s Slides on Type Replacement

• Heyde, S., Osmani, V., Schauberger, G. et al. Global parental acceptance, attitudes, and knowledge regarding human papillomavirus vaccinations for their children: a systematic literature review and meta-analysis. BMC Women's Health 24, 537 (2024). https://doi.org/10.1186/s12905-024-03377-5

• Kamolratanakul, S., Pitisuttithum, P. 2021. Human Papillomavirus Vaccine Efficacy and Effectiveness against Cancer. Vaccines (Basel). 9(12), 1413.

• Lehtinen, M., Lagheden, C., Luostarinen, T., Eriksson, T., Apter, D., Bly, A., Gray, P., Harjula, K., Heikkilä, K., Hokkanen, M., et al. 2021. Human papillomavirus vaccine efficacy against invasive, HPV-positive cancers: population-based follow-up of a cluster-randomised trial. BMJ Open. 11(12), e050669.

• Lei, J., Ploner, A., Elfström, K.M., Wang, J., Roth, A., Fang, F., Sundström, K., Dillner, J., Sparén, P. 2020. HPV Vaccination and the Risk of Invasive Cervical Cancer. New England Journal of Medicine. 383(14), 1340-1348.

• Sundström, K., Elfström, K.M. 2020. Advances in cervical cancer prevention: Efficacy, effectiveness, elimination? PLoS Medicine. 17(1), e1003035.

Click here or on the image to sign up for the IPAK-EDU Vaccine Course (Self-Paced) and learn more about vaccines than you ever thought imaginable.