To be able to prevent cervical cancer in women aged less than 45 years the quadrivalent HPV vaccine was developed [33]. Recently, the therapeutic role of the HPV vaccine has been claimed in some studies [16, 20, 21]. In the present study, the impact of prophylactic quadrivalent HPV vaccine in the treatment of women with cervical intraepithelial neoplasia (CIN 1–3) was investigated. Based on the result, a 58.7% reduction in the recurrence of CIN 1–3 was reported in women who received two or more doses of the quadrivalent HPV vaccination after the conservative treatment of CIN 1–3. Satisfactory results of therapeutic HPV vaccinations have been also reported in women with CIN 1–3 in previous clinical trials [20, 21].

At the two-year follow-up, 45.7 and 75.6% of CIN 1 lesions regressed in control and intervention groups respectively. Since CIN 1 does not pose a significant risk factor for developing CIN 3, then it is not considered for screening, or treatment [34]. Accordingly, in this study, we just included women with residual/recurrent CIN 1. The overall efficacy of two further doses of the HPV vaccine in the treatment of residual/recurrent CIN 1 was 54.9%. In accordance with these data, the efficacy of the vaccine in the prevention of recurrent CIN 1 lesions has been reported in studies 42.6% [35] and 48.3% [22].

In the present study, at the two-year follow-up, the vaccine reduced the number of women with CIN 2–3 by 75% (93 to 23 women). The overall efficacy of two further doses of the HPV vaccine in the treatment of CIN 2 and CIN 3 was 63.3 and 52.5% respectively. In line with our data, in Joura and co-workers’ study, the efficacy of the vaccination in the reduction of high-grade cervical disease was 64.9% (95% CI 20.1 to 86.3%) [22]. In addition, a prospective nonrandomized study conducted in Korea showed that the post-surgical HPV vaccination has been accompanied by a lower risk of recurrence of CIN 2. So that the recurrence of CIN 2 lesions in HPV vaccinated and non-vaccinated groups was 2.5% (9/360) vs. 7.2% (27/377), (p < 0.01) [16].

In the present study, at the two-year follow-up, 22% of CIN 2 lesions in women in intervention group persisted or progressed to CIN 3, and 27.9% of CIN 3 lesions persisted. In Tainio and coworkers’ study 3160 women with CIN 2 lesions were investigated in terms of spontaneous regression, persistence, or progression to CIN 3 or cancer. At the end of the follow-up period, 18% of CIN 2 lesions had progressed, 32% persisted, and 50% had regressed [36].

Since the single dose of the HPV vaccine has not been proven to be effective [37,38,39,40], therefore, in the present study women who received just one dose of the vaccine were excluded. The efficacy of two and three doses of the HPV vaccine in the treatment of residual/recurrent CIN 1 was 38.6 and 63.1%, respectively. The efficacy of two and three doses for the treatment of CIN 2 was 50, and 72.2%, respectively. Although the results of some studies suggest that three doses of HPV vaccination is highly more effective than two doses in preventing of occurrence of cervical neoplasia [38], but some studies reported no significant difference between two and three doses [40, 41]. In our study, we noted a big difference in efficacy with three doses of HPV vaccine versus two doses of vaccine. In line with our results, in Basu and coworkers’ study, the efficacy of three and two doses of the vaccine against high-grade lesions in recipients was 46% versus 21% [38]. Since the primary purpose of the present study was not to compare the efficacy of two or three doses of the HPV vaccine, so randomization was not performed on this basis. Therefore, this issue calls for another ethically well-formed longer studies with appropriate design.

In the present study, one woman in the control group actually developed invasive cervical cancer. While, in McCredie and co-workers’ study, invasive cervical cancer occurred in almost 30% of women with untreated CIN 3 developed over a 30-year follow-up period. Women with untreated CIN 3 were at high risk of cervical cancer, while the risk was very low in women who were receiving conservative treatment throughout [42]. The difference observed in our study with McCredie et al. study is that, in our study, all women (intervention or control group) received lesions-related treatment, including LEEP, cold-knife conization, ablation according to protocols [28]. Therefore, the effect of vaccination after the treatment of CIN 1–3 was assessed in women who missed the chance to be vaccinated before developing the disease. In fact, the vaccination is being used to force the immune system to produce antibodies that can block spontaneous HPV infection and reduces the recurrence of the CIN lesions [11, 16, 20, 22]. The results of studies show that immunizing against HPV infection is able to protect patients from precancerous cervical conditions and is very likely to reduce cervical cancer rates in the future [16, 20, 22]. Since the prevention of all types of cervical cancer is not possible with the HPV vaccine, so women still need to go for regular screening even after they have been vaccinated [43].

The side effects of the HPV vaccine in the present study were headaches, redness, and rash at the injection site. The most frequent side effect of the prophylactic quadrivalent HPV vaccine in Goncalves et al. was pain and swelling at the injection site. Other complications included fatigue, headache, fever, and gastrointestinal symptoms in a later stage [44]. Safety outcomes were similar in the various investigated groups [45, 46]. In a follow-up study conducted by Romanowski et al., a serious adverse event was reported by 30 (8%) women in the vaccine group versus 37 (10%) in the placebo group. None was considered to be related or possibly related to the vaccination, and no deaths occurred [45].

Although the present study yielded important data, the limitations are worthy of mention. Due to the high costs of the vaccine, our results are based on the evaluation of a small number of persons. The second limitation was the short duration of follow-up. The third limitation was that we disregarded the women’s HPV status (positive or negative. Finally, the women’s age range and the dosage of the vaccine were not regarded as important factors in the design of the study and their randomization to the control and intervention groups. Studies have shown that the rate of regression of lesions differs in various age groups [47]. Such that the regression rate more highly was reported among women below 30 years of age than (60% vs.11%) [36]. The fact that all women with CIN 3 received three doses of the vaccine might have influenced the results of the present study. Therefore, long-term studies of an appropriate design will be needed to investigate the long-term efficacy of the HPV vaccine in preventing the progression of cervical lesions.