A call for switching to a 1-dose 9vHPV national vaccination program in Ethiopia

Résumé

schoolgirls aged 14 years old because of the global vaccine supply constraint. The supply constraint is projected to continue for several years with many Gavi-eligible countries planning the introduction of HPV national immunization programs (5). Importantly, WHO set a goal of achieving cervical cancer elimination by 2030 worldwide. A dose-reduction vaccination approach is urgently needed if the WHO goal of cervical cancer elimination by 2030 is to be met. Largescale prospective randomized clinical trials (RCTs) in Costa Rica and India demonstrated that a one-dose (1-dose) HPV vaccine regimen induces similar long-term protection to that of multidose (3), (4). In 2022, based on these efficacy data, WHO proposed that each country could decide to implement alternative, off-label regimens, including a 2-dose schedule in all age groups or a 1dose schedule for individuals aged 9-20 years (6). Before the implementation of a 1-dose HPV vaccine regime, however, the following key policy questions should be answered based on the currently available evidence in the Ethiopian context: (i) which 1-dose vaccine type regime (1dose 4vHPV versus 1-dose 9vHPV) is optimal; (ii) does Ethiopia need locally generated evidence to make a policy switch to a 1-dose 9vHPV vaccine regime; (iii) will 1-dose 9vHPV vaccine be sufficient to offer protection to HIV-infected girls; and (iv) is the HPV vaccine uptake optimal? In this opinion paper, we provide our insights related to these key policy questions.According to the recent systematic review, HPV 16 is the most dominant HPV genotype among HPV-positive women, accounting for over 37% of HR-HPV infections while HPV18 is responsible for 4.4% of infections (7) with a combined HPV16/18 infection prevalence of 54%. The seven common non-HPV16/18 HR-HPV genotypes detected in Ethiopia were [HPV-31 (3.8%), 33(1.7%), 35(4.8%), 39 (1.9%), 45(3.5%), 52(6.8%), 58(3.1%), and 68(2.8%)] (7). The data implies that 46% of women's infections with HR-HPV genotypes in Ethiopia are related to non-HPV 16/18 genotypes. A very recent study found that HPV16 (31.8%), 31(19.1%), 52(11.8%), 58(10.9%), and 35(10%) were the most frequently detected HR-HPV genotypes while HPV18 was detected in only 2.7% of HPV-positive women (8). These data altogether suggest that vaccinating girls with the 4vHPV vaccine would protect only 54 % of infections with HR-HPV genotypes, leaving 46% of vaccinees vulnerable to infections with non-4vHPV vaccine HR-HPV genotypes.By contrast, the 9vHPV vaccine is highly efficacious in offering protection to five additional HR-HPV genotypes (9). Thus, if Ethiopia switches to the 9vHPV vaccine, over 90% of vaccinated women will likely be protected from the 9vHPV vaccine HR-HPV genotypes-related persistent infections and diseases.Given obtaining efficacy data based on virological or cervical dysplasia (disease) endpoints will take several years when vaccination given to girls before first sexual debut, the efficacy of the 1dose 9vHPV vaccine can be assessed through immunobridging trials (10). An immunobridging trial is a non-inferiority comparison of geometric mean concentrations (GMCs) of anti-HPV antibodies for specific HPV genotypes in a new population group with those in a population group in whom efficacy had been established in RCT with virological or disease endpoints. It assumes if the GMCs of antibodies between two groups are comparable, the efficacy between the two groups is comparable too. Accordingly, immunobridging RCTs on a 1-dose 9vHPV vaccine schedule have been conducted in sub-Saharan African countries where the 90% of the global cervical cancer burden occurs and dose reduction is a critical strategy for increasing HPV vaccine coverage (10).Results from RCTs conducted in Tanzania and Kenya, where like Ethiopia their populations have similar additional comorbidities (e.g., HIV, parasites, and malnutrition) that may compromise the quality and durability of vaccine-induced immune responses, proved the efficacy of 1-dose 9vHPV vaccine in preventing cervical cancer associated with infections with HPV-16, 18, 31, 33, 45, 52, and 58. Based on these established efficacy results along with the diversity of HR-HPV genotypes distribution data in Ethiopia, we are advocating a policy switch to a 1-dose 9vHPV vaccine schedule. Nevertheless, if the Ministry of Health needs prior local evidence to make the in-demand decision, conducting an immunobridging RCT study that aims to compare antibody GMC specific to HPV genotypes with the Tanzanian 1-dose 9vHPV vaccine immunobridging cohort (10) can be considered instead of waiting for several years until local efficacy data based on virological or disease endpoints will be generated.In sub-Saharan Africa, including Ethiopia, the burden of HIV infection is also high. In 2023 alone, >620,000 new HIV infections are estimated to occur in Ethiopia with women being disproportionately infected (11). Approximately 1 in 5 cervical cancers occur in women living with HIV (WLWH). Additionally, WLWH are more likely to be infected with more HR-HPV genotypes not covered by the 4vHPV vaccine (12). Considering this, WLWH will more likely benefit from the introduction of the 9vHPV vaccine. Despite accumulated evidence on immunogenicity and tolerability of 3-dose of both 4vHPV and 9vHPV vaccines in HIV-infected children and women (13), however, there is no RCT regarding the efficacy of 1-dose 9vHPV vaccine in HIVpositive individuals so far. An immunobridging study would be the fastest strategy to get approval for the use of a 1-dose 9vHPV vaccine in WLWH. Until results from immunobridging studies are publicly available, we dither advocating the use of 1-dose 9vHPV in HIV-infected girls. Instead, we recommend at least 2-dose 9vHPV vaccination over the ongoing 2-dose 4vHPV given the 9vHPV vaccine's potential to offer protection to more non-4vHPV vaccine HR-HPV genotypes (9).Besides the additional public health benefits, a mathematical model-based study suggests the costeffectiveness of the 9vHPV vaccine in Ethiopia compared to the current 2-dose 4vHPV vaccination program (14). The minimum price per dose for Gardasil 4vHPV and 9vHPV vaccines are $4.50 and $5.18, respectively (14). In Ethiopia, the estimated number of girls of age 14 years who are eligible to take the current 2-dose 4vHPV vaccine in 2023 alone is above 1.5 million (11). If Ethiopia adopts a 1-dose 9vHPV vaccine as its national HPV immunization schedule, it will save a minimum of $5.73 million per year and a total of $40.11 million by end of 2030, assuming that the vaccine uptake and coverage is 100% and the number of HPV vaccine eligible girls remain the same. And this saved money can be stretched to support vaccine delivery or building other healthcare services. Until the global vaccine shortage is circumvented and becomes affordable to low and middle-114 income countries (LMICs), including Ethiopia, we suggest switching to a 1-dose 9vHPV 115 vaccination program to accelerate the elimination of cervical cancer in Ethiopia by 2030. For HIV-infected girls, however, we recommend the use of at least a 2-dose 9vHPV vaccination schedule until evidence regarding the efficacy of 1-dose 9vHPV vaccination in WLWH are available.Switching to a 1-dose vaccination schedule can also partially circumvent the current suboptimal HPV vaccine uptake in Ethiopia.Despite its health befits, the 9vHPV vaccine is not yet included in the Gavi support list for lowincome countries (LICs). Thus, high cervical burden LICs, including Ethiopia with a high prevalence of non-4vHPV vaccine HR-HPV genotypes should request Gavi to consider the 9vHPV vaccine in its support list or seek other global international support. If Gavi requires local evidence to support switching to a 1-dose 9vHPV vaccine schedule, Ethiopia may consider conducting a pilot immunobridging RCT.

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