Target group and vaccination schedule
For the bivalent, quadrivalent and nonavalent vaccines, the vaccination schedule depends on the age and immunocompetency of the recipient. Girls < 15 years at the time of first dose: a 2-dose schedule (0, 6 months) is recommended. The two doses should ideally be separated by 6 to 12 months and the interval from the first dose should not be less than 5 months [
11]. For women aged 15 years and older, and those immunocompromised and/or HIV-infected, receiving HAART or not, a 3-dose schedule (0, 1–2, 6 months) is recommended [
11].
Whilst, studies have shown the bivalent, quadrivalent and nonavalent to be safe and immunogenic in HIV-infected women [
12] with women with HIV RNA load > 10,000 copies/ml and or CD4 count < 200 cells having lower rates of seroconversion rates, there is to date no efficacy data from HIV-infected individuals in Sub Saharan Africa. Nor is the duration of adequate antibody titers to the vaccine associated HPV types established, which precludes a boosting vaccine dosing regimen from being established. A specific aspect to consider within the sub Saharan continent, where helminths are among the major public health problems [
13], is the resultant dominant Th2 helper immune response [
14]. In turn a dominant Th2 helper immune response may further diminish the necessary Th1 response in HIV infected female and as corollary, modify the potency of the vaccine [
15].
Moreover, with HAART initiation at a higher CD4 count, seroprevalence studies should consider whether HIV-infected girls (9–14 years), who have initiated HAART at a CD4 count above 350 mm3 are immunologically non-inferior to immunocompetent girls having been administered the recommended two-dose schedule recommended for the bivalent, quadrivalent, and nonavalent HPV vaccine in that age group.
The impact of the bivalent or quadrivalent vaccine in the HIV-infected female population in sub-Saharan Africa will depend on the prevalence of HPV 16 and HPV 18. A recent meta-analysis (2016) on the distribution of pHR/HR HPV genotypes in HIV-infected women in Kenya reported a pooled estimated prevalence of HPV 16 and 18 of 61% in women with ICC [
16], in presence of multiple HPV co-infections. Whilst HPV-16 and HPV-18 pose much higher cancer risks than any other HPV type and replacement by a nononcogenic type or an oncogenic type is not expected to have any major consequences in a general population [
17], it is unclear what this shift in a HIV-infected population may entail. Given the wide spectrum of HPV genotypes reported in HIV-infected women, the threat of type replacement [
18] by hitherto less prevalent HPV genotypes, including HPV 52, 56 along with the potentially high risk of HPV 53 after the successful elimination of HPV 16 and 18, underscores the importance of broader primary prevention programs.
One-dose schedule
A study combining data from two large trials found similar protection against HPV 16 and 18 from a single bivalent vaccination as from the current two and three dose schedules [
19]. Moreover, early findings from an Indian study indicate that a single dose of quadrivalent HPV vaccine is immunogenic and provides lasting protection against HPV 16 and 18 infections similar to the three and two dose vaccine schedules [
20].
Apart from helping to overcome programmatic barriers in resource-poor settings, if HPV vaccines could be delivered as single dose, while retaining their efficacy against the most oncogenic HPV types 16 and 18, it may open a great opportunity to extend the reach of protection to more people [
21].
However, protection against HPV types phylogenetically-related to HPV 16, HPV 31 and 33, and against HPV45, which is phylogenetically-related to HPV 18, probably attributable to cross-neutralizing antibodies, may be lower with alternate vaccine schedule as compared with the standard three dose regimen [
22]. Despite the potential loss of cross-protection, a single dose may be sufficient to reduce the number of ICC worldwide by 70% [
23]. It is unknown whether a one-dose HPV vaccination schedule can confer similar protection to HIV-infected women with a moderately reconstituted immune system. Should studies suggest that similar protection can be extended to women with moderately reconstituted immune systems, cost-effectiveness analyses must be undertaken to compare a one dose regimen to a two/three-dose vaccine regimen in HIV-infected girls/women based on the epidemiology of pHR/HR HPV genotypes within each context.
Catch-up campaigns
In 2016, the WHO revised its position to recommend delivering vaccination to multiple age cohorts of girls aged 9–14 years in resource-poor settings in order to increase HPV vaccine uptake and bring forward the benefits of vaccination in the population [
24], following the rapid effectiveness seen in many industrialized countries where HPV vaccine introduction has been extended to the age of 26.
Assuming affordable vaccine cost and knowledge of the local distribution of HPV genotypes, additional catch-up rounds may be beneficial to older HIV-infected girls, whose future access to cervical screening is uncertain and who are at risk of acquiring and transmitting multiple HPV co-infections. It has to be recognised, though, that vaccination campaigns are not meant to replace routine immunisation services if sufficient coverage is to be maintained [
25] and that as female school enrolment in many countries drops after primary school, a school-based vaccination strategy may not be successful in capturing older vulnerable HIV-infected girls.
However, it is unclear whether, among women infected with HPV, the residual benefit of preventing infection with HPV types contained in the vaccine to which the women have not yet been exposed would be sufficient to warrant vaccination [
26]. The lesser impact expected of the HPV vaccine in older HIV-infected women due to a potential higher risk of prior exposure to vaccine targeted genotypes, may be compensated by the potential of the HPV vaccine to prevent recurrence of CIN 2–3 among women treated for HSIL [
27], possibly due to generated antibodies providing protection against new infection or reinfection from other areas of the genital tract with vaccine targeted types. Estimates for the incidence of disease recurrence after treatment vary widely from 25 to 55% at 12 months in HIV-infected women compared with 5–16% in HIV-negative women [
28].
Prior to the implementation of a catch-up campaign, a cost-effectiveness study should be performed. This would entail comparing the number of cases of HSIL and cancer, with the associated costs of treatment and lives/quality of life lost, that would occur with screening alone, single cohort vaccination only, or single cohort plus catch up vaccination.