Advancements in mRNA Vaccines: A Promising Approach for Combating Human Papillomavirus-Related Cancers

Human papillomavirus (HPV) is a widespread sexually transmitted infection. These viruses are characterized by their small size, lack of outer envelope, and possession of double-stranded DNA. HPV infects various types of epithelial cells in the skin and mucous membranes, causing multiple health issues. ¹ The primary mode of transmission of HPV is through sexual contact, including vaginal, anal, or oral sex. It is highly contagious and can be transmitted even when no visible symptoms appear. HPV, a member of the Papillomaviridae family, is also known to cause anogenital and cutaneous warts. It is also associated with the development of oropharyngeal cancers (affecting the oral, tonsil, and throat areas) and anogenital cancers, including cervical, anal, vulvar, vaginal, and penile cancers. ² Genital HPV infection is widespread, affecting 75% to 80% of people worldwide, irrespective of age or gender, making it the most common sexually transmitted infection globally. ³

According to data from 2015 to 2019, approximately 47 199 new cases of HPV-associated cancers are reported annually in the United States. Of these cases, around 26 177 occur among women, while about 21 022 occur among men. HPV is widely believed to be responsible for over 90% of anal and cervical cancers, around 70% of vaginal cancers and vulvar cancers, and more than 60% of penile cancers. Traditionally, oropharyngeal cancers have been associated with tobacco and alcohol use, but recent studies indicate that around 70% of oropharyngeal cancers may be linked to HPV. ⁴

In the light of all the clinical manifestations of HPV, it is necessary to prevent and treat it. The most notable measures taken against HPV include vaccines. Vaccines are medical interventions used to prevent and treat various diseases. They work by stimulating the immune system to recognize and combat specific viruses or cancer cells. Examples include the HPV vaccine, which reduces the risk of cervical cancer, and the Hepatitis B vaccine, which lowers the risk of liver cancer. Vaccines have been instrumental in preventing diseases and are now being explored for their potential in treating cancer. ⁵

HPV vaccines protect against specific strains of the virus. The quadrivalent vaccine, known as Gardasil, safeguards against HPV types 16 and 18, responsible for approximately 70% of cervical cancer cases in the UK, and HPV types 6 and 11, the main culprits behind most genital warts. Similarly, the bivalent vaccine, called Cervarix, offers cancer-preventive properties against HPV 16 and 18. Another option is the nonavalent vaccine, Gardasil 9, which guards against HPV types 16, 31, 18, 33, 45, 52, and 58, along with those addressed by the quadrivalent vaccine. These vaccines prevent HPV-related diseases, notably cervical cancer, with specific administration guided by country-specific recommendations. ⁶

Prophylactic vaccines like Gardasil and Cervarix exhibit high efficacy (90-98%), high immunogenicity, and the ability to generate memory B cells. ⁷ However, these vaccines are not effective in treating pre-existing malignancies and infections, as they function by deploying antibodies against the L1 capsid protein. This protein is expressed before viral shedding, rendering these vaccines ineffective against pre-existing lesions. In contrast, therapeutic vaccines generate cell-mediated immunity rather than antibodies, thereby acting against infected cells. Additionally, prophylactic vaccines necessitate large-scale deployment for success, which is a costly process. This is why, up until mid-2016, only 8% of low-to middle-income countries had introduced the HPV vaccine, compared to 71% of high-income countries. ⁸ Thus, therapeutic vaccines can play a key role in treating individuals already infected by preventing progression and recurrence.

mRNA vaccines as therapeutic vaccines represent the way forward, as they do not interfere with recipient DNA due to their short half-life. Cells degrade mRNA shortly after the expression of the encoded antigen. The manufacturing cost is low, and safe administration makes it more favorable. These vaccines do not contain a live virus and can be manufactured rapidly, as they do not involve cell culture for production. ⁹ Routes of administration for mRNA vaccines include systemic delivery, where the vaccine is injected into the bloodstream (eg, via intravenous injections). Local injections, administered at the site of action, are an option to avoid side effects of systemic delivery. Targeted delivery, involving direct administration into the target tissue (eg, internodal injection), can also be utilized. ¹⁰ Therefore, a wide choice of intravenous, subcutaneous, intradermal, intramuscular, and intranodal modes of administration is available.

One such vaccine is mRNA vaccination which involves the engineering of stable forms of mRNA and administering them into the body. mRNA instructs the body to manufacture proteins that stimulate immune responses when exposed to the same proteins in tumors or viruses. This process occurs through translation by dendritic cells, which then present the antigens to T cells and other immune cells to initiate an immune response. Eventually, T cells eliminate cancer cells and virus-infected body cells. ¹¹

Cancers have also been targeted from this approach for nearly a decade, where naked or vehicle-loaded mRNA that express tumor antigens in antigen-presenting cells (APCs) and subsequently result in stimulating innate/adaptive immunity are used. ¹² But, until now, the US Food and Drug Administration (FDA) has approved no mRNA cancer vaccine. It is because of instability issues like the mRNA sequence if injected unprotected, it would be identified by the immune system and destroyed. A solution to this was recognized in coronavirus vaccine trials where lipid nanoparticles encased the mRNA. ¹¹

Recently, a novel study that involved three mRNA vaccine sequences being tested in mice produced groundbreaking findings. These mRNA vaccines targeted cancers caused by HPV infections (head, neck, and cervical cancers), and it was found that all three were successful in removing HPV-related cancers in the mice. Further, it was even concluded that a single dose was also effective in fighting the tumor, and in most mice, the cancer didn’t rebound. The three vaccines were unmodified nonreplicating mRNA vaccine, nucleoside-modified nonreplicating mRNA vaccine, and self-amplifying mRNA vaccine (Table 1). These vaccines resulted in the production of gDE7 protein through translation. Production of this protein prepared the immune system to fight HPV by early recognition and attack after coming across the E7 protein from HPV-16. It involved the stimulation of antigen-specific immune cells called CD8-positive T cells and would lead to the killing of the protein. Killing this protein would stop the progression of cancer, which is why earlier attempts targeting this protein have also been made. Fortunately, these three outperformed the earlier attempts of using gDE7 protein-based and DNA-based gDE7 vaccines. ⁶

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Table 1.

Summary of mRNA Vaccine Types and Their Efficacy in Targeting HPV-Related Cancers.

Vaccine Type	Results
Unmodified nonreplicating mRNA vaccine. 6	Production of gDE7 protein through translation. 6
Nucleoside-modified nonreplicating mRNA vaccine. 6	Production of gDE7 protein through translation. 6
Self-amplifying mRNA vaccine. 6	Production of gDE7 protein through translation. 6
Personalized mRNA vaccine in combination with an immune checkpoint inhibitor. 11	Targeting patients with head and neck cancers that HPV causes. 11

Another clinical trial currently undergoing involves a personalized mRNA vaccine in combination with an immune checkpoint inhibitor targeting patients with head and neck cancers that HPV causes. It showed promising results as cancer in 2 among the 10 patients went away, and in 5 patients, it shrank. To further study the responses thoroughly, the study was extended to 40 participants. This is another step towards effective cancer vaccinations, enabling personalized immunotherapy by attacking specific cancer cells based on their abnormal molecular features. ¹¹

Previously, immunizations targeted tumor antigens common to various cancers, but biological tumor heterogeneity means there is massive variability in tumor antigens of tumors of different tissues. The identification of tumor-specific mutations has been made possible by high-throughput sequencing techniques. This process involves the comparison of healthy and malignant tissues of a patient; hence, germline variants are not mistaken for being non-epitopes. The shifted focus on targeting tumor-associated antigens (TAAs) with high specificity is what is known as personalized cancer vaccines. ¹³ Recently, an advancement in the treatment of pancreatic cancer with a personalized mRNA vaccine was noted. An NIH-funded research team removed Pancreatic Ductal Adenocarcinoma (PDAC) from 19 people. The tumor samples from these individuals were handed to BioNTech; they identified proteins from the tumor that triggered an immune response and used that information to design a personalized mRNA vaccine for each patient, each targeting 20 neoantigens (Table 1). After a year and a half, patients with a strong T cell response showed significant results by staying cancer-free, and in one patient, the T cells produced by this vaccine even eliminated a tumor that spread to the liver. ¹⁴

Despite the progress, challenges remain, including the instability of mRNA vaccines due to being attacked by innate immunogenicity, however, this was catered to in the above mice model using self-modifying and nucleoside-modified nonreplicating mRNA vaccine. Furthermore, the vaccines encased in lipid nanoparticles offer another way of protection. So, all these advancements after the mRNA vaccine approval for COVID-19 and promising results from the mice model are leading the way to HPV cancer-free population with more investments at stake. Researchers and health care professionals should keep exploring the inherent, innate immunity of mRNA and continue modifying mRNA to attain diverse and potent control over cancers. Further investments and research in this field will be instrumental in realizing these prospects.