HPVワクチンは効果だけではなく、安全性も気になるところですね。ついでに少し触れておきましょう。
国内の状況
厚生労働省での副反応検討部会での資料はこちらから入手可能です。国内での副反応報告状況なども「資料」から辿ることができます。
国内の状況はすでに報道もされている通りのようですが、詳細なデータが確認できます。資料をざっと目を通すと、海外データは2011年までのものは確認できますが、新しいデータは反映されているのかどうか、よくわかりませんでした。
海外では最近でも安全性データが発表されています。
海外の報告
HPVワクチンの安全性については、海外で３つの総説が最近発表されています。順にみていきましょう。
システマティックレビュー（Gonçalves, 2014年） *1
研究の概要
HPVワクチンの研究参加者がHPVワクチン *2 を接種すると、プラセボまたはワクチン接種なしに比べて有害事象は多かったか、を検討した二重盲検ランダム化比較試験のシステマティックレビュー。
主な結果
12研究、29,540人が対象。結果は表を一部改変して引用する。
どちらかと言えば軽度な有害事象に焦点を当てていますが、プラセボまたはワクチン接種なしに比べて多い傾向がわかります。
この研究では重篤な有害事象という項目はありませんでした。
導入部分には、このような記載があります。
Severe AE, such assevere headache with hypertension, gastroenteritis and bron-chospasm, were described in 0.5%.
重篤な有害事象は0.5%のみで、ほとんどが局所の副反応のみである（だから今回は調べない）といった論調。ぼくらの関心とはちょっとずれている印象ですね。
レビュー（Nakalembe, 2015年） *3
低～中所得国で実施されたHPVワクチンに関する安全性と効果を検討したレビュー。10のランダム化比較試験、2の観察研究、3の横断研究が抽出されています。このうち、安全性の結果についてのみ一部抜粋して引用します。
In most of these studies, assessments for safety were based on both solicited and unsolicited local symptoms like pain and swelling at injection site as well systemic symptoms like arthralgia, fatigue, fever, gastrointestinal symptoms, headache, myalgia, rash, or urticaria (Table 2).
In some of the studies, new onset of chronic diseases (NOCDs), medically significant conditions (MSCs), pregnancies and their outcomes were also assessed [14, 16, 17, 20]. In all these studies (Table 2), the HPV vaccines were found to be generally safe and well tolerated among the participants. Injection site pain was the most common complaint which appeared more frequently among the vaccine recipients in most of the studies while in others there was no apparent difference in the incidence of AEs between the vaccine and non vaccine groups (Table 2). In all the studies, there were no vaccine related serious adverse events (Table 2).
低～中所得国においてもやはり局所の副反応や軽度の全身症状ばかりで、HPVワクチンによる重篤な有害事象の報告はないようです。
レビュー（De Vincenzo, 2014年） *4
気になる部分を一部抜粋して引用します。
There is a wide range of immunomediated disease with different etiologies that may be triggered by genetic or infective conditions. Vaccination stimulates the immune system to produce antigen-specific immunity. Because AD *5 etiologies also involve stimulation of the immune system, it has been suggested that vaccination may trigger ADs. The mechanism most frequently proposed is molecular mimicry, in which antigens of the host are recognized as being similar to antigens of the vaccine, thus provoking the development of autoantibodies. Moreover, potentiation or activation of previously unrecognized ADs in susceptible individuals is a theoretical concern related to the immunostimulatory effects of new adjuvants. [58]
自己免疫疾患との関連について書かれています。新しいアジュバントの関与についても触れられていました。
With regard to the previous consideration, a comparative analysis of data on HPV vaccines’ serious ADs is complex. A list of principal studies on serious AEs in the long-term safety evaluation of HPV vaccines is reported and detailed in Table 4.[42,55,58–64] A registry-based cohort study of 997,585 girls aged 10–17 years conducted in Sweden and Denmark compared AEs in 296,826 girls receiving qHPV vaccine with the incidence of the conditions in unvaccinated girls, and did not find evidence supporting an association between the vaccine and autoimmune, neurological, or venous thromboembolism AEs.[63] Other surveillance studies have likewise not found an increased risk of autoimmune disorders associated with qHPV vaccine.[61,64]
Recently, a pooled analysis of large-scale and long-term safety data from the 42 completed/ongoing clinical trials with bHPV vaccine has been published. Overall, 31,173 adolescent girls/women received bHPV vaccine alone (HPV group), 2,166 received bHPV vaccine coadministered with another vaccine, and 24,241 were controls, with a mean follow-up of 39 months. The incidence of unsolicited AEs reported within 30 days after any dose was similar between the HPV and control groups (30.8% and 29.7%, respectively). During the entire study period, reports of medically significant conditions (25.0% and 28.3%, respectively) and serious AEs (7.9% and 9.3%, respectively) were also similarly distributed between groups. Potential immune-mediated diseases within 1 year were reported by 0.2% of bHPV vaccines and controls.[58]
自己免疫疾患との関係は複雑で証明することは難しいと前置きしながらも、これまでの研究では関与を示唆するデータはない、とのこと。
現時点では仮説の域を出ない、ということでしょう。
さらに日本の報告についても記載されています。
The incidence of chronic pain resembling complex regional pain syndrome reported in Japan (24 cases reported to date) is being investigated, but so far the expert advisory committee has not been able to ascertain a causal relationship with vaccination. [66,67]
Having reviewed all available data, the International Federation of Gynecology and Obstetrics (FIGO) Gynecologic Oncologic Committee and Subcommittee for Cervical Cancer Prevention support the continued administration of the HPV vaccines in appropriate populations. [68]
今のところFIGO（国際産婦人科連合）では接種推奨に変更はない、としています。
FIGO
2013年のFIGOの声明文を確認しておきましょう。CRPSに関する部分のみ抜粋引用します。
FIGO Statement on HPV Vaccination Safety | FIGO
Complex Regional Pain Syndrome (CRPS)
- AE following immunisation commonly include local pain at the injection site, but the development of CPRS, has only been described in children immunised with rubella and hepatitis B vaccines. CPRS is a clinical syndrome that affects one or more extremities and is characterised by persistent pain disproportionate to the initiating event, which is often minor trauma
- 4 cases were reported to the Surveillance of Adverse Events following Vaccination in the Community after it was initiated in Victoria, Australia 2007, and one case from the UK
- 4 of the 5 cases met the criteria for CPRS and all resolved within 5 days to 7 months without recurrence or consequence
- It is important to be aware of this syndrome which can be triggered by any injury to the extremity, including intra-muscular injection.
- Cases of chronic pain in the extremities have been reported in Japan where over 8 million doses of HPV vaccine have been distributed – the issue is being intensively investigated but data received to date does not convincingly implicate HPV vaccination, as opposed to any other type of vaccination
日本の慢性疼痛の事例については、HPVワクチンが原因と断定できない、との記載です。
CRPSについては、オーストラリアで４例、英国で１例発生していますが、いずれも回復している、とのことです。
こちらも国内の動向を含め、どのような行方になるか目が離せないところです。
*1:Gonçalves AK, Cobucci RN, Rodrigues HM, de Melo AG, Giraldo PC. Safety, tolerability and side effects of human papillomavirus vaccines: a systematic quantitative review. Braz J Infect Dis. 2014 Nov-Dec;18(6):651-9. doi: 10.1016/j.bjid.2014.02.005. Epub 2014 Apr 27. Review. PubMed PMID: 24780368.
*2:２価または４価ワクチン
*3:Nakalembe M, Mirembe FM, Banura C. Vaccines against human papillomavirus in low and middle income countries: a review of safety, immunogenicity and efficacy. Infect Agent Cancer. 2015 Jun 12;10:17. doi: 10.1186/s13027-015-0012-2. eCollection 2015. Review. PubMed PMID: 26075018; PubMed Central PMCID: PMC4465311.
*4:De Vincenzo R, Conte C, Ricci C, Scambia G, Capelli G. Long-term efficacy and safety of human papillomavirus vaccination. Int J Womens Health. 2014 Dec 3;6:999-1010. doi: 10.2147/IJWH.S50365. eCollection 2014. Review. PubMed PMID: 25587221; PubMed Central PMCID: PMC4262378.
*5:autoimmune disease (AD) such as hypothyroidism, rheumatoid arthritis, Behçet’s syndrome, Raynaud’s disease, type 1 diabetes, and vitiligo.
