Therapeutic DNA Vaccines against HPV-Related Malignancies: Promising Leads from Clinical Trials.

In 2014 and 2021, two nucleic-acid vaccine candidates named MAV E2 and VGX-3100 completed phase III clinical trials in Mexico and U.S., respectively, for patients with human papillomavirus (HPV)-related, high-grade squamous intraepithelial lesions (HSIL). These well-tolerated but still unlicensed vaccines encode distinct HPV antigens (E2 versus E6+E7) to elicit cell-mediated immune responses; their clinical efficacy, as measured by HSIL regression or cure, was modest when compared with placebo or surgery (conization), but both proved highly effective in clearing HPV infection, which should help further optimize strategies for enhancing vaccine immunogenicity, toward an ultimate goal of preventing malignancies in millions of patients who are living with persistent, oncogenic HPV infection but are not expected to benefit from current, prophylactic vaccines. The major roadblocks to a highly efficacious and practical product remain challenging and can be classified into five categories: (i) getting the vaccines into the right cells for efficient expression and presentation of HPV antigens (fusion proteins or epitopes); (ii) having adequate coverage of oncogenic HPV types, beyond the current focus on HPV-16 and -18; (iii) directing immune protection to various epithelial niches, especially anogenital mucosa and upper aerodigestive tract where HPV-transformed cells wreak havoc; (iv) establishing the time window and vaccination regimen, including dosage, interval and even combination therapy, for achieving maximum efficacy; and (v) validating therapeutic efficacy in patients with poor prognosis because of advanced, recurrent or non-resectable malignancies. Overall, the room for improvements is still large enough that continuing efforts for research and development will very likely extend into the next decade.

Inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.

Concerns about vaccine safety are an important reason for vaccine hesitancy, however, limited information is available on whether common adverse reactions following vaccination affect the immune response. Data from three clinical trials of recombinant vaccines were used in this post hoc analysis to assess the correlation between inflammation-related solicited adverse reactions (ISARs, including local pain, redness, swelling or induration and systematic fever) and immune responses after vaccination. In the phase III trial of the bivalent HPV-16/18 vaccine (Cecolin®), the geometric mean concentrations (GMCs) for IgG anti-HPV-16 and -18 (P<0.001) were significantly higher in participants with any ISAR following vaccination than in those without an ISAR. Local pain, induration, swelling and systemic fever were significantly correlated with higher GMCs for IgG anti-HPV-16 and/or anti-HPV-18, respectively. Furthermore, the analyses of the immunogenicity bridging study of Cecolin® and the phase III trial of a hepatitis E vaccine yielded similar results. Based on these results, we built a scoring model to quantify the inflammation reactions and found that the high score of ISAR indicates the strong vaccine-induced antibody level. In conclusion, this study suggests inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.

Human Papillomavirus Vaccination After COVID-19.

The current global novel coronavirus disease 2019 (COVID-19) pandemic threatens to derail the uptake of human papillomavirus (HPV) vaccination in low- and lower-middle income countries with major disruptions to routine immunization and the introduction of new vaccines delayed. This has a major impact on the World Health Organization cervical cancer elimination strategy, where it is dependent on HPV vaccination as well as cervical cancer screening and treatment. We discuss current opportunities and barriers to achieve high uptake of HPV vaccination in low- and lower-middle income countries as well as the impact of COVID-19. Implementation of 4 key recommendations for HPV vaccination in low- and lower-middle income countries is needed: increased global financial investment; improved vaccine supply and accelerated use of a single-dose schedule; education and social marketing; and adoption of universal school-based delivery. With the commitment of the global health community, the adoption of these strategies would underpin the effective elimination of cervical cancer.

Contemplating HPV vaccination in Japan during the time of COVID-19.

The Coronavirus Disease 2019 (COVID-19) pandemic has been growing, including in Japan where it has been estimated that as many as 3.1% of patients positive for new CoV strain SARS-CoV-2 might die of COVID-19-related respiratory failure. Meanwhile, human papillomavirus (HPV) is spreading in Japan. The fatality rate for HPV-associated cancers after infection with HPV is as much as that for COVID-19 in Japan, although the time to disease is much longer for HPV. Among advanced countries, the cervical cancer screening rate in Japanese females is very low. The Japanese Ministry of Health, Labor and Welfare (MHLW) suspended its official recommendation for HPV vaccination in June 2013 due to alleged adverse post-vaccination events in several young girls, such as chronic pain and motor impairment, which were repeatedly reported in the media. Subsequently, the rate for vaccinating girls plummeted from approximately 70% to the current rate of 1% or less. Women should accept HPV vaccination for the eventual prevention of cervical cancer with the same passion they are for COVID-19 testing.

The European response to the WHO call to eliminate cervical cancer as a public health problem.

The age-standardised incidence of cervical cancer in Europe varies widely by country (between 3 and 25/100000 women-years) in 2018. Human papillomavirus (HPV) vaccine coverage is low in countries with the highest incidence and screening performance is heterogeneous among European countries. A broad group of delegates of scientific professional societies and cancer organisations endorse the principles of the WHO call to eliminate cervical cancer as a public health problem, also in Europe. All European nations should, by 2030, reach at least 90% HPV vaccine coverage among girls by the age of 15 years and also boys, if cost-effective; they should introduce organised population-based HPV-based screening and achieve 70% of screening coverage in the target age group, providing also HPV testing on self-samples for nonscreened or underscreened women; and to manage 90% of screen-positive women. To guide member states, a group of scientific professional societies and cancer organisations engage to assist in the rollout of a series of concerted evidence-based actions. European health authorities are requested to mandate a group of experts to develop the third edition of European Guidelines for Quality Assurance of Cervical Cancer prevention based on integrated HPV vaccination and screening and to monitor the progress towards the elimination goal. The occurrence of the COVID-19 pandemic, having interrupted prevention activities temporarily, should not deviate stakeholders from this ambition. In the immediate postepidemic phase, health professionals should focus on high-risk women and adhere to cost-effective policies including self-sampling.