Bibliometric Analysis of The Scientific Literature on Human Papillomavirus Vaccine Clinical Trials: Analysis of PubMed Database

Background: Cervical cancer is the 4 th most common cancer in the world caused by human papillomavirus (HPV). A preventive measure for cervical cancer is immunization with the HPV vaccine. Hence globally many clinical trials on HPV vaccines are being performed to prevent HPV infection. This bibliometric analysis is done to determine the trend of clinical trials on HPV vaccines worldwide over the years


INTRODUCTION
Human papillomavirus is the cause of cervical cancer, which is the 4 th most common type of cancer in the world and the 2 nd most common type of cancer in women in India. 1,2 There are about 150 genotypes of human papillomavirus, based on DNA sequence analysis, causing HPV infection with different clinical presentations. 3 Among them, the most common genotypes are types 6, 11, 16, and 18. Types 6 and 11 also cause anogenital warts (low-risk HPV infection) and types 16 and 18 cause cancer of the vagina, vulva, penis, anus, and oropharynx (high-risk HPV infection) by suppression of tumor suppressor gene. HPV infection spreads through sexual contact and by direct skin contact. HPV usually results in subclinical infection where the individual develops immunity, and the virus leaves the system in 2 years. But in some cases, with high-risk genotypes, the individual may develop cancer. Complicated HPV infection occurs in immunocompromised patients. 4,5 Vaccines are highly effective in preventing infection when it is administered before the individual is exposed to the virus. It is recommended for adolescent females. There are 3 types of vaccines available to offer protection against the infection. They are bivalent, quadrivalent, and nonvalent vaccines. The bivalent vaccine (Cervarix-manufactured by GSK Biologicals) is effective against types 16 and 18 of HPV. The quadrivalent vaccine (Gardasil manufactured by Merck) is effective against types 6, 11, 16, and 18. The nonvalent vaccine (Gardasil 9 manufactured by Merck) is effective against 9 different genotypes of HPV-6, 11, 16, 18, 31, 33, 45, 52, and 58. 1,6 Numerous clinical trials are being conducted worldwide in different groups of populations to check the vaccine efficacy in that specific population. This is greatly helping in combating the disease. The result of these clinical trials is being published in many peer-reviewed journals. The pattern of publication of scientific evidence on the HPV vaccine clinical trials can be studied by bibliometric analysis. Here, we have done a bibliometric analysis of the scientific literature on HPV vaccine clinical trials from the Pub-Med database.

METHODOLOGY
Data Source: We retrieved HPV vaccine clinical trial articles from the PubMed database (Mar 1999 -Sept 2022). The articles were published by around 188 institutions from 39 countries. The PubMed database is a free resource that provides access to abstracts and citations that have been issued in biomedical and life sciences journals and maintained by the National Center for Biotechnology Information (NCBI), at the U.S. National Library of Medicine (NLM), located at the National Institutes of Health (NIH).
We used some keywords in the PubMed database to retrieve the articles of our interest. They were "effi-cacy", "HPV vaccine", "gardasil", "gardasil 9" and "cervarix" Search Strategy: We used the following search strategy in the PubMed database (efficacy) AND [(HPV vaccine) OR (gardasil) OR (gardasil 9) OR (cervarix)] Filters: Clinical Trial, Randomized Controlled Trial Study selection and data management: We downloaded the data as an Excel file. The three independent reviewers reviewed the articles. We carefully evaluated the articles retrieved on HPV vaccine clinical trials and included them for analysis. We included data by reviewing the articles apart from the data downloaded for analysis under a few other variables. A final check on the data was done to not miss any differences in the same kind of data. For example, articles published by one author under different names (Giuliano AR and Anna R Giuliano) were categorized under the same name (Guiliano AR).
Eligibility criteria: We included only English articles that were published and indexed in the PubMed database under the keywords "efficacy", "HPV vaccine", "gardasil", "gardasil 9" and "cervarix". Only articles on HPV vaccine clinical trials were retrieved.
Data extraction: We extracted bibliometric data from the articles downloaded. The bibliometric data under the following variables were extracted, corresponding author name, corresponding author affiliation, number of authors, corresponding author's country, publication year, article citations, and the journal in which the article was published. We retrieved the citation information from Google Scholar and journal information on the publisher's name, impact factor, journal's country of origin, frequency of publication, and the main theme of the journal.
Data analysis: Network and overlay visualization were done with the help of VOSviewer software. Visualization of country-wise publication was done using Maptitude software. Keywords cloud was done using the ChartExpo software in MS Excel. Other basic analysis was done using MS Excel. Analysis was done under the following variables, corresponding author name, corresponding author affiliation, number of authors, corresponding author's country, coauthorship analysis, publication year, article citations, co-occurrence of keywords, and the journal in which the article was published. We ranked the top 10 data under every variable.

RESULTS
We extracted 308 articles from the PubMed database and obtained 296 clinical trial articles after removing the non-relevant ones. Publications were done by 39 countries across the world (Figure 1a). The majority of the papers were published by institutions in the United States of America (USA) among 39 countries (n=112, 37.8%). Followed by the USA, the highest number of publications were by China, Canada, Finland, and the UK. The listed top 10 countries pub-lished more than two-thirds of the total publications (n=232, 78.3%) (Figure 1b).    The majority of articles were published by more than five authors (n=252, 85.13%) ( Figure 2). The corresponding author, Lehtinen M from the Department of Infections and Cancer, German Cancer Research Center has done the most number of publications (n=7, 2.3%) ( Table 2).  (Table 3).
The first three highly cited articles had more than 2000 citations. "A controlled trial of a human papillomavirus type 16 vaccine" authored by Koutsky LA has the highest citation of 2467 published in the New England Journal of Medicine (Table 4)     Keywords provided by the authors that occurred for five times and more in the PubMed database were used for analysis. The database contained a total of 963 keywords, out of which 137 met the threshold. The commonly used keywords were "humans" with total link strength of 3890 that was used 307 times that has a strong link with the keyword "human papillomavirus" with the link strength of 117 followed by "antibodies, viral" with the link strength of 113 (figure 5a). A word cloud was created with the keywords that occurred five times and more ( figure 5b). It shows that that the keyword "humans" is commonly used followed by "female", "papillomavirus vaccines" and "papillomavirus infections".

DISCUSSION
The articles were published in the context of HPV vaccination trials among different populations across the world, of different age groups, some with associated co-morbidity, and others among the special population to study the safety, immunogenicity, and long-term effects. All these trials are being conducted to prevent even the thinnest chance of anyone being infected. The clinical trials have also helped to fix the vaccine dosage and frequency of administration. Few studies have also aimed to study the vertical transmission of the antibodies from mother to fetus following vaccination in mothers. 7,8 According to these studies, there is potential placental transmission of antibodies from mother to fetus.
The earliest study on the HPV vaccination was done in 1999 by C J Lacey et al 9 It was a phase IIa study. According to this study, a fusion protein vaccine was developed with HPV 6 L2E7 and Alhydrogel for the treatment of genital warts, given in 3 doses. Then emerged the era of prophylactic HPV vaccines. FDA approved three prophylactic vaccines for HPV infection following successful clinical trials. Gardasil was approved in 2006, Cervarix in 2009, and Gardasil 9 in 2014. 10 These vaccines provide essential protection against the infection by generating neutralizing antibodies but are ineffective when the individual is already infected.
In recent years, trials are being conducted in the development of therapeutic HPV vaccines. Therapeutic vaccines act by activating cellular immunity and eliminate the infected cells by acting on the oncoproteins E6 and E7. This can therefore be used as an adjunct to the surgical approach to cancer and prevent a recurrence. Different types of therapeutic vaccines are Live vector-based vaccines (2 subtypes-bacterial and viral vaccines), peptide and protein vaccines (2 subtypes-long and short peptide vaccines), nucleic acid vaccines (2 subtypes-DNA and mRNA vaccines), and Whole-cell vaccines (2 subtypes-Dendritic cell and Tumor vaccines). 11,12 Here, we could see the evolution of HPV vaccines over the years tried and implemented through clinical trials. The first authors in the top ten articles were also the corresponding authors. Corresponding author Lehtinen M had the highest number of publications followed by Einstein MH. Half of the corresponding authors had at least four publications. More than two-thirds of the papers were published by more than 5 authors.
The National Cancer Institute of the USA has done extensive research on the HPV vaccines. The NCI is a USA federal government agency exclusively for cancer research. NCI is the part of National Institute of Health (NIH), a unit of the Department of Health and Human Services (HHS). The NCI is funding and conducting clinical trials on HPV vaccines in the USA. 13 "A controlled trial of a human papillomavirus type 16 vaccine" authored by Koutsky LA has the highest citation of 2467 published in the New England Journal of Medicine. 14 According to this article, the study participants were administered HPV 16 virus-like particles in three doses. Following immunization, the vaccine protected against the HPV 16 infection which eventually reduces the incidence of cervical cancer caused by the HPV 16 virus. 15,16 The top 3 highestcited articles were published in the New England Journal of Medicine with a high impact factor of 176.079.

CONCLUSION
This bibliometric analysis of the HPV vaccine clinical trial shows a steady increase in the clinical research publication of the HPV vaccine. The USA has the highest number of publications, also the institution with the highest number of publications (National Cancer Institute) is from the USA. All of these research activities on the HPV vaccine across the world are ultimately aiding in reducing the incidence of the HPV infection. The strength of this study is that we have included all articles on HPV clinical trials irrespective of the year of publication to analyse the trend of publication and the advances over the years. The limitation of this study is that we have included articles from only the PubMed database.