Potential Effects of Human Papillomavirus Type Substitution, Superinfection Exclusion and Latency on the Efficacy of the Current L1 Prophylactic Vaccines

Abstract

There are >200 different types of human papilloma virus (HPV) of which >51 infect genital epithelium, with the ~14 of these classed as high-risk being more commonly associated with cervical cancer. During development of the disease, high-risk types have an increased tendency to develop a truncated non-replicative life cycle, whereas low-risk, non-cancer-associated HPV types are either asymptomatic or cause benign lesions completing their full replicative life cycle. HPVs can also be present as non-replicative so-called "latent" infections and they can also show superinfection exclusion, where cells with pre-existing infections with one type cannot be infected with a different HPV type. Thus, the HPV repertoire and replication status present in an individual can form a complex dynamic meta-community which changes with respect to both time and exposure to different HPV types. In light of these considerations, it is not clear how current prophylactic HPV vaccines will affect this system and the potential for iatrogenic outcomes is discussed in light of recent outcome data.

Keywords: CIN; HPV; L1; latency; prophylactic vaccine; superinfection exclusion; type replacement.

Figure 1

Normal full HPV life cycle.

Figure 2

Truncated HPV life cycle and neoplasia. The E2 ORF is disrupted by integration into host DNA, which prevents the production of infectious virions, upregulates expression E6 and E7 and suppresses expression of L1.

Figure 3

Estimated number of diagnosed CIN2+ cases by HPV type and age group in United States from 2008 to 2016.

Figure 4

CIN 2-associated HPV types detected in New Zealand women from 2013 to 2016.

Figure 5

Incidence of invasive cervical cancer in the UK 1993–2017. (Source: Cancer Research UK.) (A) Total for all age groups; (B) Stratified between different age groups.

Figure 6

Age stratified incidence of cervical cancer in Australia from 1982 to 2015. Since the introduction of cervical screening in 1991, the incidence in the 25–49 years age range declined until 2001 then started to increase from 2009 until 2015. It is speculated that restructuring these results into the age groupings used for the UK data, as shown in Figure 5B, may prove informative.

Figure 7

Five-year averaged age-standardised incidence of cervical cancer in New Zealand from 1987 to 2017.

Figure 8

Incidence of cervical cancer in Sweden from 1960 to 2017.

Figure 9

Potential for dissemination of vaccine-related changes in HPV types between vaccinated and unvaccinated women. Illustrates how vaccine-induced changes in the prevalence of different HPV types in vaccinated women could be disseminated to unvaccinated women via partner-mediated sexual transmission.