Addressing Unmet Medical Needs Through Tailored Vaccine Design: The Importance of Adjuvant Systems - It is now possible to combine antigens with specific adjuvant systems to create more-effective vacc


Addressing Unmet Medical Needs Through Tailored Vaccine Design: The Importance of Adjuvant Systems
It is now possible to combine antigens with specific adjuvant systems to create more-effective vaccines.

BioPharm International Supplements

The Challenge of a Vaccine Against HPV to Prevent Cervical Cancer

Worldwide, cervical cancer is the second most prevalent cancer in women between 15 and 45 years of age, and there are nearly 500,000 new cases per year.16 It is the third leading cause of female cancer deaths.17 The disease is provoked by persistent infection with oncogenic strains of HPV.

Infection with oncogenic types of HPV presents some challenges for developing an effective vaccine:18

First, the infection is local and limited to the mucosal level. The virus has learned to largely evade the immune system. Consequently, the immune responses aiming at controlling or eradicating the virus are attenuated after natural infection.

Second, natural immune responses following infection with oncogenic HPV types may not always protect against subsequent HPV infection or eliminate the risk of a persistent HPV infection

Also, because infection can occur throughout a woman's sexually active life, it is important to protect women throughout their lifetime.

Therefore, an HPV vaccine has to ensure protective efficacy through a systemic immune response even though the virus enters the body through the mucosal route and remains localized there.

Experimental data have shown that high levels of HPV-specific neutralizing serum antibodies are key to providing reliable protection.19–20 The optimal vaccine should therefore induce a strong and long-lasting antibody response as well as immune memory.21

Given the above challenges, the effect of introducing an adjuvant system was investigated in pre-clinical studies and compared to classical adjuvantation with aluminium salt. Preclinical and clinical studies demonstrated that the cervical cancer vaccine, Cervarix, formulated with AS04 (composed of aluminium hydroxide and MPL, an immunoenhancer and agonist of the TLR4 receptor) induces a stronger and more sustained immune response with higher antibody levels and frequency of memory B cells than the same formulation with aluminium hydroxide alone.2,22 In a comparative study with Gardasil, a vaccine formulated with amorphous aluminum hydroxyphosphate sulfate salt, Cervarix was shown to provide higher serum anti-HPV-16 and -18 neutralizing antibody titers and higher circulating HPV-16 and -18 specific memory B cell frequencies.23

Subsequent clinical studies have shown that the vaccine provides high-level, high-quality neutralizing antibody responses lasting up to 6.4 years.24 This finding concurs with sustained, long-term efficacy (6.4 years) against incident infections, persistent infections, and precancerous lesions associated with HPV-16 and -18, and evidence of cross-protection against incident infections caused by other oncogenic HPV types in HPV-naïve women aged 15 to 25 years.25

The vaccine also has shown a strong and sustained immune response in women aged 10 to 55 years. In a broad Phase 3 study in women aged 15 to 25 years (enrolment without screening for HPV infections) vaccination confirmed high efficacy (up to 98%) against cervical intraepithelial neoplasia lesions of grade 2 or worse (CIN2+) related to HPV types 16 and 18 in the total vaccinated cohort for efficacy. Cross-protection was demonstrated against CIN2+ with a 100% vaccine efficacy in the case of HPV-31 and -45 (the third and fourth most frequent oncogenic types, respectively) and a 68.2% vaccine efficacy against the five most frequent oncogenic types (HPV 31/33/45/52/58) in the total vaccinated cohort for efficacy.26–27

In addition, the vaccine induced high levels of HPV-16 and -18 antibodies in serum and cervicovaginal secretions (CVS) for at least 24 months following the first vaccine dose in females aged 15 to 55 years. In all age groups, a strong correlation was observed between serum and CVS antibody titers for both HPV types 16 and 18.28

More than 20,000 study participants have received at least one dose of AS04-adjuvanted HPV vaccine, and clinical trials have demonstrated that this vaccine is generally well tolerated. Rates of solicited local and general symptoms were higher in the adjuvanted vaccine group than in the control groups. However, compliance with the three-dose schedule was high and did not differ between groups. Pain at the injection site was the most frequently reported symptom. Most frequently reported general symptoms were headache, fatigue, and myalgia. Solicited symptoms were mild to moderate in intensity and short-lived, and rates of unsolicited and serious adverse events were similar between the adjuvanted vaccine group and the control group.29–30

In conclusion, the AS04-adjuvanted HPV-16/18 cervical cancer vaccine has been able to induce the immunological profile needed. It has been shown to elicit high and sustained serum-neutralizing antibodies that transudate/exudate to the site of HPV infection in sufficiently high concentrations to bind HPV viruses and prevent infection. The strong immune priming observed post-vaccination may be indicative of the observed high and sustained protection and cross-protection, and brings a solid immunological basis for long-term protection.

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