Academic literature on the topic 'Prophylactic cancer vaccine'

In the past, vaccines were defined as prophylactic entities. Today, there are two types of vaccines: prophylactic for prevention, and therapeutic for the treatment of infections or cancers. Therapeutic cancer vaccine, in fact, represents an option for active immunotherapy for the treatment of late-stage and/or prevention of recurrent diseases.1

The last 20 years is one of the most remarkable periods in the fight against cancer, with the realization that some human papillomaviruses are causally related to cancer and with the development of the vaccine against human papillomavirus infections. This is a historical event in medicine and the prophylactic human papillomavirus vaccines have provided powerful tools for primary prevention of cervical cancer and other human papillomavirus-associated diseases. This is very important as human papillomavirus infection is probably the most common sexually transmitted infection worldwide, and over one million women develop associated cancer yearly, which is about 5% of all female cancers, and half of them die of their disease. Cancers associated with oncogenic human papillomaviruses, mostly HPV16 and 18, include cervical cancer (100%), anal cancer (95%), vulvar cancer (40%), vaginal cancer (60%), penile cancer (40%), and oro-pharingeal cancers (65%). In addition, pre-cancers such as genital warts and the rare recurrent respiratory papillomatosis are also preventable by vaccination. Currently, the human papillomavirus vaccines have the potential to significantly reduce the burden of human papillomavirus associated conditions, including prevention of up to 70% of cervical cancers. Two prophylactic human papillomavirus vaccines are currently available worldwide: a bivalent vaccine (types 16 and 18), and a quadrivalent vaccine (types 6, 11, 16, and 18). Randomized controlled trials conducted on several continents during the last 10 years have demonstrated that these vaccines are safe without serious side effects; they are highly immunogenic and efficacious in preventing incident and persistent vaccine-type human papillomavirus infections, high grade cervical, vulvar and vaginal intraepithelial neoplasia and so on. In addition, the quadrivalent vaccine has been shown to prevent genital warts in women and men. The vaccine is most effective when given to human papillomavirus naive girls. The human papillomavirus vaccines have been incorporated into national immunization programs in 22 European countries. Routine vaccination is recommended for girls aged between 9 and 13 years and catch-up vaccination for females between 13 and 25 years of age. There is no excuse not to incorporate the vaccines into the Hungarian national immunization program. Albeit vaccination is expensive, it is cost-effective in the long run definitely. Anyway, vaccination is a matter of the specialty and the national health program, but not of business. We all are obliged to prevent human suffering. Orv. Hetil., 2013, 154, 603–618.

Background Men and women with HIV infection are at increased risk of developing cancers associated with human papillomavirus (HPV). The two licensed prophylactic HPV vaccines protect against de novo infection with HPV-16 and HPV-18, which cause the majority of HPV-associated cancers. Currently, no vaccine efficacy data are available for persons with HIV infection. Nevertheless, some countries have implemented specific HPV vaccination recommendations for HIV-positive populations. To specifically recommend prophylactic HPV vaccination in people with HIV, the vaccines must be safe and immunogenic in immunosuppressed people at a high risk of HPV infection. This review aims to summarise the current knowledge from published HPV vaccine trials in HIV-infected populations, to compile scheduled and ongoing HPV vaccine trials with HIV-positive study populations and to extrapolate the relevant knowledge about HPV vaccine efficacy in HIV-negative populations to an HIV context. Methods: The databases PubMed, Scopus and ClinicalTrials.gov were searched for peer-reviewed articles and scheduled or ongoing clinical HPV vaccine trials enrolling HIV-positive persons. Results: Current data indicate that prophylactic HPV vaccines are safe and immunogenic in different HIV-positive populations (children, female adolescents, adults). Increased immunogenicity has been reported in persons on antiretroviral therapy compared with antiretroviral-naïve persons, whereas no clear association has been found between CD4+ cell count at immunisation and vaccine response. Several scheduled and ongoing HPV vaccine trials aim to determine vaccine efficacy against disease endpoints in HIV-infected study populations. Conclusion: Prophylactic HPV vaccination appears safe, immunogenic and, by extrapolation, likely to reduce HPV-associated cancer development among persons with HIV infection.

Human papillomavirus (HPV) infection is the cause of squamous cell carcinoma of the uterine cervix. This causative relationship has provided the rationale and incentive for development of a prophylactic vaccine. Such a vaccine, if found to be effective, could reduce the need for cervical cancer screening and have a profound effect on the incidence of cervical and other anogenital cancers. This review begins by examining the basic biological and epidemiological principles relevant to the development of HPV preventative vaccines. It then summarises studies examining the use of vaccines to prevent HPV infection in animals and humans, and, finally, discusses some of the unanswered issues surrounding vaccine development against HPV infection and cervical cancer.

Objective: A review of current knowledge on the efficacy of HPV (human papillomavirus) HPV vaccination against pre-cancers and cervical cancer. Methods and results: HPV infection is probably the most common sexually transmitted disease and the cause of approximately 5% of all human cancers. Currently, three prophylactic vaccines against HPV infection are on the market: bivalent Cervarix, quadrivalent Gardasil (formerly Silgard) and nonavalent Gardasil9. The Czech Republic is one of the countries with a national vaccination program where HPV vaccination is covered by health insurance for girls and boys aged 13–14 years. Extensive scientific data on the efficacy of the vaccines clearly demonstrate significant efficacy against the development of cervical pre-cancers for all three vaccines. According to a high-certainty evidence of the Cochrane database, the efficacy of HPV vaccines against cervical intraepithelial neoplasia grade 2 or 3 associated with HPV 16, 18 compared with placebo in girls and women aged 15–26 is 99%. There is also moderate-certainty evidence that HPV vaccines reduce the risk of adenocarcinoma in situ for approximately 90% for the same population. Initial data also demonstrate a direct impact on reducing the incidence of invasive cervical cancer in vaccinated individuals. In addition, quadrivalent and nonavalent vaccines are highly effective in preventing genital warts. Conclusion: All three available prophylactic vaccines show high efficacy in preventing the development of cervical lesions. Effi cacy is highest against lesions caused by vaccine genotypes and the highest efficacy is achieved in the HPV naive population. Key words: human papillomavirus – HPV – vaccination – HPV vaccine – efficacy – cervical precancerous – cervical carcinoma

Abstract Passive immunotherapy has become an effective adjunct for the treatment of HER2/neu-overexpressing breast cancers, as patients can respond well to monoclonal antibodies such as trastuzumab (anti-HER-2/neu antibody therapy). However, patients with late-stage disease, who often become immunosuppressed are unlikely to respond, motivating the development of new prophylactic vaccines. To this end, we have developed an injectable, polymer-based cryogel vaccine containing living, attenuated HER-2/neu-overexpressing breast cancer cells. The cryogel-based vaccine mimics key aspects of bacterial infection and directly controls immune-cell trafficking and activation in the body. This system provides a sustained release of GM-CSF to recruit host dendritic cells (DCs) to the porous material, and subsequently presents breast cancer antigens and TLR9 ligand CpG oligonucleotides to activate the resident DCs. Subcutaneous injection of the cryogel vaccines provide potent prophylactic protection against mammary cancer in mice, consistent with significantly higher titers of Her-2/neu-specific antibodies compared to the humoral responses induced by bolus injection of irradiated GM-CSF-secreting breast tumor cells. The cryogel-based vaccines induced a 70-fold increase in antibody production compared to untreated mice and 100% survival was achieved in vaccinated mice. The cryogel-based vaccines represent a promising tool for the development of novel active immunotherapeutic approaches to cancer.

SUMMARYHuman papillomavirus (HPV) is the necessary cause of cervical cancer, the fourth most common cancer and cause of cancer-related death in females worldwide. HPV also causes anal, vaginal, vulvar, penile, and oropharyngeal cancer. Prophylactic HPV vaccines based on recombinantly expressed virus-like particles have been developed. Two first-generation, U.S. Food and Drug Administration (FDA)-approved vaccines prevent infections and disease caused by HPV16 and HPV18, the two HPV genotypes that cause approximately 70% of cervical cancer, and one of these vaccines also prevents HPV6 and HPV11, the two HPV genotypes that cause 90% of genital warts. A next-generation vaccine, recently approved by the U.S. FDA, targets HPV16, HPV18, and five additional HPV genotypes that together causes approximately 90% of cervical cancer as well as HPV6 and HPV11. In clinical trials, these vaccines have shown high levels of efficacy against disease and infections caused by the targeted HPV genotypes in adolescent females and males and older females. Data indicate population effectiveness, and therefore cost effectiveness, is highest in HPV-naive young females prior to becoming sexually active. Countries that implemented HPV vaccination before 2010 have already experienced decreases in population prevalence of targeted HPV genotypes and related anogenital diseases in women and via herd protection in heterosexual men. Importantly, after more than 100 million doses given worldwide, HPV vaccination has demonstrated an excellent safety profile. With demonstrated efficacy, cost-effectiveness, and safety, universal HPV vaccination of all young, adolescent women, and with available resources at least high-risk groups of men, should be a global health priority. Failure to do so will result in millions of women dying from avertable cervical cancers, especially in low- and middle-income countries, and many thousands of women and men dying from other HPV-related cancers.

Abstract High-grade bronchial dysplasia is a marker for high risk of lung squamous cell carcinoma (SCC). Cancer vaccines targeting dysplasia could prevent the progression to SCC and decrease lung cancer incidence in population at risk. In order to develop a vaccine to prevent lung SCC we need to identify antigens and epitopes within them able to elicit a potent Type I anti-tumor immune response. One caveat to develop a prophylactic vaccine targeting dysplasia is that driver mutations (neo-antigens) are not known. Many mutations appear late in lung cancer and are not shared between patients. However, upregulated non-mutated proteins are needed from the early stages of cancer to support the new proliferation requirements of the cells, are common between patients and are good candidates for a preventive vaccine. Type I CD4+ T cells (Th1) secreting interferon-gamma (IFN-g) are necessary for enhanced function of antigen presenting cells, epitope spreading and activation of cytotoxic CD8+ T cells. However, non-mutated tumor self-antigens frequently induce Type II CD4+ T cells (Th2), which secrete cytokines that inhibit the function of Th1 and CD8+ T cells. To develop a prophylactic lung cancer vaccine we have: (1) searched in public datasets genes that are upregulated in bronchial dysplasia and maintain upregulation in SCC; (2) used web based algorithms for class II epitope prediction followed by functional ELISPOT screening to identified epitopes eliciting IFN-g (Th1) and/or IL-10 (Th2) responses; (3) selected only the Th1 epitopes (excluding the Th2 epitopes) to evaluated efficacy of the vaccines in a chemically induced rodent model of SCC. Preliminary data shows that we can reduce dysplasia frequency in vaccinated mice treated with the carcinogen.

The use of proteins or peptides as immunogens is attractive for the development of vaccines, especially cancer vaccines, but requires efficient and safe adjuvant formulations to overcome their intrinsic weak immunogenicity. Although dozens of different adjuvants have been shown to be effective in preclinical and clinical studies, alum remains the only one approved for human use in the USA and the most employed worldwide, but it turned out to be inefficient in cancer vaccine formulations. Indeed, the prerequisites for an ideal cancer adjuvant differ from conventional adjuvants. Since cancer vaccines target self-antigens, the ideal cancer adjuvant must be extremely potent to circumvent immune tolerance, but it must also be safe to avoid autoimmune reactions. Of note, recent studies indicate that effective therapeutic and preventive cancer vaccines require the induction of a more balanced T helper 1 (Th1)/Th2 immune response, characterized by the presence of a strong cytotoxic CD8+ T lymphocyte (CTL) activity, and the production of IgG subclasses with specific effector functions. For example, efficient tumor prevention in mice is associated with high levels of IgG2a and IgG2b subclasses, which are considered the most potent inducers of complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in rodents. To solve all these problems, new generation vaccines often incorporate toll-like receptors (TLRs) agonists. Among them, natural polymers (NPs) that can act as damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), are emerging as a new efficient class of vaccine adjuvants due to their ability to orchestrate the cross-talk between innate and adaptive immunity. In particular, NPs induce the maturation of dendritic cells (DCs) and finely regulate the balance between Th1 and Th2 responses, thus inducing potent and long-lasting humoral and cellular responses. Moreover, they are biocompatible, biodegradable, non-toxic, non-immunogenic, and non-inflammatory. This project aimed at validating our NP, called NPX for patent constraints, as a new TLR agonist and carrier of immunogens for the design of more efficient and safer cancer vaccines, and comparing its adjuvanticity with alum. To this aim, NPX was chemically linked to the extracellular domain (ECD) of the rat form of the epidermal growth factor receptor (rHER2/neu), or to short peptide sequences derived from the ECD of rHER2/neu, and the resulting bioconjugates were used for immunization of both BALB/c and BALB-neuT transgenic mice. In this work, we demonstrated that NPX has an extremely satisfactory safety profile, as no local side effects were observed in vaccinated mice. Moreover, NPX induced strong antigen-specific immune reactions very efficiently. In fact, even though both alum- and NPX-adjuvanted formulations induced high humoral immune responses against rHER2/neu, NPX-vaccinated BALB/c mice disclosed IgG titers that were about two-fold higher than those calculated for alum. Of note, only conjugation with NPX induced a detectable humoral response against rHER2/neu-derived peptides. Both adjuvants induced high production of different IgG subclasses, but despite similar IgG1 titers NPX-vaccinated mice disclosed also higher IgG2a and IgG2b levels. The strong elicitation of the three IgG subclasses and the production of both Th1 and Th2-type cytokines such as IL-12p70, IFN-γ, IL-2, IL-6, and IL-10, confirmed the ability of NPX to induce a balanced Th1/Th2 response. Moreover, the different quality and quantity of IgG subclasses, and their superior ability to recognize rHER2/neu in its native conformation likely reflected on the better functionality of NPX-induced antibodies in triggering complement-mediated specific lysis of rHER2/neu-positive cells. Interestingly, NPX not only induced humoral responses that persisted over time, but also selected mature B cell clones secreting antibodies with an improved ability to bind rHER2/neu in its native conformation and to mediate effector functions. The robust immune responses induced by NPX proved to be effective in both the prophylactic and therapeutic settings; indeed, NPX-adjuvanted vaccine formulation prevented and significantly delayed tumor growth in tumor challenged mice. Interestingly, antitumor responses seemed in part to be mediated by NPX ability to induce also CTL responses, which were detected only in NPX-vaccinated groups. Finally, while both alum- and NPX-adjuvanted vaccines proved to be successful in breaking tolerance against rHER2/neu in BALB-neuT transgenic mice, NPX-vaccinated mice displayed IgG titers that were two-fold higher than those observed with alum. Interestingly, in transgenic mice NPX vaccination resulted in a better Th1/Th2 balance than in BALB/c mice. However, only NPX-induced antibodies were able to recognize rHER2/neu in its native conformation. This likely explains the capacity of NPX-based vaccination to protect from or delay the growth of spontaneous tumors in BALB-neuT mice, whereas alum completely failed to induce any protective response. Taken together, our data show that NPX is a safe and powerful adjuvant that could be exploited for the development of new HER2/neu vaccination strategies. In fact, NPX is effective in enhancing the magnitude, breadth, quality, and longevity of specific humoral and cellular immune responses to antigens, without causing toxicity. Importantly, these effects can be achieved even with a strongly reduced antigen dose.
L’utilizzo di proteine o peptidi come immunogeni ha sempre rappresentato un’attrattiva per la creazione di vaccini, in particolare per i vaccini a scopo antitumorale; ciononostante, questo genere di formulazione richiede l’impiego di adiuvanti immunologici efficienti e sicuri che siano in grado di potenziare la scarsa immunogenicità degli antigeni stessi. Sebbene dozzine di adiuvanti si siano dimostrate efficienti in ambito preclinico e clinico, l’allume rimane il principale adiuvante ad uso umano impiegato in tutto il mondo, nonostante abbia dimostrato scarsa efficienza nell’ambito della vaccinazione antitumorale. I prerequisiti di un adiuvante antitumorale sono di fatto diversi da quelli dei classici adiuvanti. I vaccini antitumorali hanno infatti come target antigeni self, e dunque l’adiuvante antitumorale deve essere abbastanza potente da superarne la tolleranza immunologica, ma deve anche essere sicuro in modo da evitare fenomeni avversi di tipo autoimmune. Studi recenti hanno dimostrato che affinché i vaccini tumorali preventivi e terapeutici siano efficaci, si devono indurre risposte sia di tipo T helper 1 (Th1) che Th2, in grado di indurre sia una forte attività litica da parte dei linfociti CD8+ T citotossici (CTL) che la produzione di sottoclassi anticorpali capaci di mediare particolari funzioni effettrici. Ad esempio, nel topo è stata dimostrata una correlazione tra prevenzione tumorale e presenza di alti livelli di immunoglobuline IgG2a e IgG2b, considerate le più efficienti nell’induzione di citotossicità complemento-dipendente (CDC) e di citotossicità cellulo-mediata anticorpo-dipendente (ADCC). Per adempiere a tutte queste richieste, le nuove generazioni di vaccini spesso incorporano nella propria formulazione degli agonisti dei toll-like receptors (TLRs). Tra questi agonisti, i polimeri naturali (NP), che agiscono come damage-associated molecular patterns (DAMPs) o pathogen-associated molecular patterns (PAMPs), stanno emergendo come una nuova classe di efficienti adiuvanti immunologici grazie alla loro capacità di mediare l’interazione tra il sistema immunitario innato e adattativo. In particolare, essi sono in grado di indurre la maturazione delle cellule dendritiche (DCs) e di regolare accuratamente il bilancio tra le risposte di tipo Th1 e Th2, al fine di indurre potenti e durature risposte umorali e cellulari. Gli NP sono inoltre biocompatibili, biodegradabili, non tossici, non immunogenici e non infiammatori. Questo progetto di ricerca si è focalizzato sulla validazione del polimero naturale da noi sviluppato, cui ci riferiamo col termine NPX a causa di vincoli brevettuali, come nuovo agonista di TLR e veicolo di immunogeni per la creazione di vaccini antitumorali più efficienti e sicuri, comparando il suo profilo di adiuvanticità con quello dell’allume. A questo scopo, abbiamo coniugato NPX con il dominio extracellulare (ECD) del recettore 2 per il fattore di crescita epidermico di ratto (rHER2/neu) o con peptidi a breve sequenza amminoacidica derivati dall’ECD stesso. I bioconiugati così sintetizzati sono stati utilizzati per la vaccinazione di topi BALB/c e di topi transgenici BALB-neuT. In questo lavoro abbiamo innanzitutto dimostrato che NPX possiede un profilo d’azione estremamente sicuro, in quanto i topi immunizzati con tale adiuvante non hanno manifestato segni di tossicità a livello locale. NPX si è inoltre rivelato estremamente efficiente nell’indurre forti risposte immunitarie antigene-specifiche. Infatti, sebbene entrambi gli adiuvanti abbiano stimolato con successo elevate risposte umorali contro rHER2/neu, i topi BALB/c immunizzati con NPX hanno prodotto titoli di IgG doppi rispetto a quelli riscontrati nel gruppo trattato con l’allume. Inoltre solo NPX è riuscito a indurre la produzione di anticorpi in risposta alla vaccinazione con peptidi derivanti dalla porzione extracellulare del recettore. Entrambi gli adiuvanti hanno prodotto alti livelli delle differenti sottoclassi di anticorpi IgG; tuttavia, nonostante la produzione di IgG1 sia paragonabile, i livelli di IgG2a e IgG2b sono risultati nettamente maggiori negli animali vaccinati con NPX. Le elevate concentrazioni delle tre sottoclassi anticorpali e la produzione di citochine sia di tipo Th1, quali IL-12p70, IFN-γ e IL-2, che di tipo Th2, come IL-6 e IL-10, hanno confermato la capacità di NPX di indurre una risposta Th1/Th2 bilanciata. La differente qualità e quantità degli anticorpi prodotti e la loro migliore capacità di riconoscere il recettore nella sua conformazione nativa, probabilmente si riflettono nella migliore funzionalità degli anticorpi indotti da NPX nell’attivare la lisi cellulare rHER2/neu-specifica mediata dal complemento. In particolare, NPX si è dimostrato efficace non solo nell’indurre risposte umorali durature, ma anche nel selezionare cloni maturi di linfociti B secernenti anticorpi dotati di una migliore capacità di riconoscere il recettore nella sua forma nativa e di mediare le proprie funzioni effettrici. Le elevate risposte immunitarie indotte da NPX si sono dimostrate efficienti nell’ambito sia della vaccinazione preventiva che terapeutica, prevenendo o ritardando in entrambi i contesti la crescita tumorale nei topi inoculati con il tumore. Tali risposte sembrano inoltre essere almeno in parte dovute all’azione dei CTL, la cui presenza è stata riscontrata solamente negli animali immunizzati con NPX. Sia la vaccinazione con NPX che quella con l’allume si sono dimostrate in grado di rompere la tolleranza contro il recettore espresso costitutivamente nei topi transgenici BALB-neuT. Il gruppo vaccinato con NPX ha prodotto titoli anticorpali doppi rispetto al gruppo allume e un profilo di risposta Th1/Th2 ancora più bilanciato rispetto a quanto osservato nei topi BALB/c. Comunque, solo gli anticorpi indotti da NPX si sono dimostrati capaci di riconoscere il recettore nella sua conformazione nativa, e ciò spiegherebbe come questo tipo di vaccinazione riesca a conferire protezione o indurre ritardo nella crescita tumorale spontanea nei topi BALB-neuT. Al contrario, la vaccinazione con l’allume ha completamente fallito nell’indurre una qualsiasi risposta tumorale protettiva. Nell’insieme, i risultati ottenuti indicano che NPX è un adiuvante sicuro ed efficace, potenzialmente utilizzabile per la creazione di vaccinazioni antitumorali HER2-specifiche. Abbiamo infatti dimostrato che NPX migliora l’entità, l’ampiezza, la qualità e la longevità delle risposte immunitarie umorali e cellulo-mediate rispetto all’allume, senza causare effetti tossici e permettendo inoltre di utilizzare dosi ridotte di antigene.

abstract: Cancer is one of the most serious global diseases. We have focused on cancer immunoprevention. My thesis projects include developing a prophylactic primary and metastatic cancer vaccines, early cancer detection and investigation of genes involved in tumor development. These studies were focused on frame-shift (FS) antigens. The FS antigens are generated by genomic mutations or abnormal RNA processing, which cause a portion of a normal protein to be translated out of frame. The concept of the prophylactic cancer vaccine is to develop a general cancer vaccine that could prevent healthy people from developing different types of cancer. We have discovered a set of cancer specific FS antigens. One of the FS candidates, structural maintenance of chromosomes protein 1A (SMC1A) FS, could start to accumulate at early stages of tumor and be specifically exposed to the immune system by tumor cells. Prophylactic immunization with SMC1A-FS could significantly inhibit primary tumor development in different murine tumor models and also has the potential to inhibit tumor metastasis. The SMC1A-FS transcript was detected in the plasma of the 4T1/BALB/c mouse tumor model. The tumor size was correlated with the transcript ratio of the SMC1A-FS verses the WT in plasma, which could be measured by regular RT-PCR. This unique cancer biomarker has a practical potential for a large population cancer screen, as well as clinical tumor monitoring. With a set of mimotope peptides, antibodies against SMC1A-FS peptide were detected in different cancer patients, including breast cancer, pancreas cancer and lung cancer with a 53.8%, 56.5% and 12.5% positive rate respectively. This suggested that the FS antibody could be a biomarker for early cancer detection. The characterization of SMC1A suggested that: First, the deficiency of the SMC1A is common in different tumors and able to promote tumor initiation and development; second, the FS truncated protein may have nucleolus function in normal cells. Mis-control of this protein may promote tumor development. In summary, we developed a systematic general cancer prevention strategy through the variety immunological and molecular methods. The results gathered suggest the SMC1A-FS may be useful for the detection and prevention of cancer.
Dissertation/Thesis
Ph.D. Molecular and Cellular Biology 2012

Chapter 6 reviews briefly the role of infections as causal agents in cancer, describes anti-hepatitis B virus (HBV) immunization as the first cancer vaccine paradigm, and finally focuses on the latest paradigm of prophylactic vaccination against human papillomavirus (HPV) infection as the new front in cancer prevention.

In 1992 Lorincz et al. were the first to evaluate the clinicopathologic correlation with 11 recently identified human papillomavirus (HPV) genotypes: 31, 33, 35, 42, 43, 44, 45, 51, 52, 56, and 58. Using cervical samples from 8 studies that included specimens from 2627 women, HPV genotypes were categorized by the likelihood of association with grades of cervical neoplasia (from normal to cancer). These findings were the basis of the determination that (a) HPV causes cervical cancer, (b) detection of the cancer associated HPV genotypes could identify women at risk for cervical pre-cancer and cancer, and (c) a prophylactic HPV vaccine should include protection against (at least) HPV 16 and 18.