Serum’s HPV vaccine non-inferior to Gardasil: study

Cervavac HPV vaccine was found to be safe and non-inferior to Merk’s Gardasil vaccine

A phase-2/3 trial of Serum Institute of India’s human papillomavirus (HPV) vaccine Cervavac conducted at 12 tertiary care hospitals across India in girls and boys aged 9-14 years has found the vaccine to be safe and non-inferior to a comparator vaccine Gardasil manufactured by Merck. The Cervavac vaccine is a quadrivalent vaccine that targets four HPV subtypes — 6, 11, 16, and 18, and was compared with the Gardasil vaccine which contains the same four HPV subtypes. The trial was carried out between September 2018 and February 2021. The results were published recently in the journal The Lancet.

The trial found that in adolescent girls and boys, two doses of the Serum’s Cervavac vaccine generated nearly double the antibody response against HPV subtypes 16 and 18 compared with the response generated with Merck’s Gardasil vaccine in young adult women; non-inferiority against HPV types 6 and 11 was also shown in the trial.

While Serum’s Cervavac vaccine was administered to boys and girls aged 9-14 years in the intervention arm, the control arm had men and women aged 15-26 years who received the comparator vaccine Gardasil. The intervention arm had 738 girls and 369 boys and received two doses of the Cervavac vaccine, while the control arm had 819 women and 381 men and received three doses of the Gardasil vaccine. The geometric mean titre (GMT) of antibodies against HPV subtypes 6, 11, 16, and 18 generated by the Serum’s Cervavac vaccine in girls and boys aged 9-14 years was compared with the geometric mean titre of antibodies generated by Gardasil vaccine in women aged 15-26 years.

The effectiveness of the HPV vaccine is generally higher when given to boys and girls at a younger age.A studythat compared the effectiveness of HPV vaccine in different age groups found that 17 studies showed the highest vaccine effectiveness in the youngest age group. It found that vaccine effectiveness estimates for younger adolescents aged 9-14years ranged from 74-93% whereas in adolescents aged 15-18 years, the effectiveness ranged from 12-90%.

“We used immunobridging approach for licensure of Serum’s vaccine. This is based on WHO’s recommendations for the evaluation of HPV vaccines. Immune responses observed with the new vaccine are compared with those obtained in an efficacy proven population. For Gardasil, efficacy is proven in women aged 15-26 years. Therefore, we compared the immune response of our vaccine to the efficacy proven population — women of age 15-26 years. With this approach, efficacy of the licensed vaccine is bridged to the comparator vaccine,” Dr. Umesh Shaligram, Executive Director – R&D, Serum Institute and a co-author of the paper says in an email to The Hindu.

Immunobridging is an important methodology that is used to support the extrapolation of efficacy from one formulation to another formulation, one population (for example, children prior to sexual debut in whom efficacy cannot be assessed due to ethical and feasibility reasons) to another population wherein the efficacy has been proven, or dosing schedule (alternative dosing regimens) based on comparison of relevant immune responses. By comparing immune responses, the efficacy observed with a specific licensed HPV vaccine may be bridged to a candidate vaccine.

On why the Serum’s Cervavac vaccine administered to boys and girls aged 9-14 is compared with Garasil given to women aged 15-26 years, Dr. Shaligram says: “For [recipients] aged 9-14 years, one has to immune bridge with the efficacy proven population. Therefore, immune responses in 9-14 girls and boys were compared with women aged 15-26 years receiving Gardasil as a primary endpoint, and this bridges efficacy to these age groups also.This is again in accordance with the WHO guidance. We have also compared [the antibody titres] in girls and boys aged 9-14 years who received Cervavac versus girls aged 9-14 years who were administered Gardasil, as a secondary endpoint.”

Explaining further the reason why the immune responses in boys and girls in the 9-14 years age group (intervention arm) are compared with the immune responses in women aged 15-26 years, Dr. Shaligram says: “For HPV vaccines, the principal target group is young adolescents who have not yet become sexually active. Regulatory authorities agreed that it was not feasible to conduct efficacy trials in this young population due to constraints surrounding evaluation of genital sampling and requirement of a very long duration of follow-up.” He further adds: “For the Gardasil vaccine too, for 9-14 years, efficacy was extrapolated based on immunobridging to 15-26 years age group. We have followed the same design as per the WHO guidance.”

As per the paper, boys who received Serum’s Cervavac vaccine could not be compared with the male population receiving Gardasil vaccine as the “comparator quadrivalent HPV vaccine is not licenced in India for boys and men”.

As per aSeptember 2022 PIB release, 1,25,000 cases of cervical cancer are diagnosed each year in India, and over 75,000 women die annually due to cervical cancer. While 70% of cervical cancer are caused by HPV subtypes 16 and 18 worldwide, in India, the two subtypes account for 83% of cervical cancer.