MC

ED

Volume 10

May

2024

HECK

N 29
o

Editorial

Healthy vaccinee effect:a key bias in observational studies

Review
HPV vaccines increase total and cancer mortality
without evidence of HPV-related cancer decrease

CONTENTS (MAY 2024, Vol. 10, No. 29)
Editorial
Healthy vaccinee effect: a key bias in observational studies

Review
HPV vaccine increase total and cancer mortality without evidenceof HPV-related cancer decrease● RCTs show increased cancer and total mortality● All observational studies failed to provide evidence forinvasive cancer prevention● Column: Healthy vaccinee effect in observational studies

MED CHECK

2

3
5
8
12

May. 2024/ Vol.10 No.29 ・ Page 1

aaa

ED
HECK

Editorial

M
C

Healthy vaccinee effect: a key bias in observational studies
In a randomized controlled trial (RCT), the baseline characteristics of the intervention and thecontrol group are essentially the same. A statistically significant reduction in the risk of events in
the intervention group compared with control group can be considered as efficacy. On the other

hand, an increased risk can be considered as a harm of the intervention. However, in a cohort
study, it is inevitable that the baseline characteristics of the two groups are different leading to abiased occurrence of events. Biased factors which affect both the selection of interventions and theoccurrence of outcomes are called “confounding factors”. In order to avoid these confounding biases,
various statistical methods have been developed including standardization, multivariate analysis using
Cox proportional hazards model, propensity score matching method and the prior event rate ratio
adjustment method for “unmeasured confounding”.

Among confounding biases, “healthy vaccinee effect (HVE)” or more generally, “healthy user bias
(HUB)” is one of the most important confounding biases that should be taken into account in any

observational study. The theoretical basis of this bias was discussed in detail as a confounding bias by
Fine and Chen in 1992 and preliminarily by MedCheck in 2016 (MedCheck in English No5). Jackson et al
discussed that adjustment for diagnosis code variables did not control this bias. However, it could be

Editorial

well adjusted by the prior event rate ratio adjustment method. The mortality rate ratio or incidence
rate ratio immediately after vaccination could be used for a proxy of a prior event rate ratio as HVE/HUB.

The PubMed search found 10 studies on HVE/HUB among 2151 studies on “influenza vaccine
effectiveness cohort studies” and 3 studies on HVE/HUB among 2386 studies on “SARS-CoV-2 vaccine
effectiveness cohort studies”. However it did not find any study on HVE/HUB among 592 “HPV vaccine
effectiveness cohort studies”.

This issue has extensively studied the effectiveness and harm of HPV vaccine examining longterm follow-up reports of randomized controlled trials. In addition it has examined the data fromobservational studies on effectiveness claiming that HPV vaccine reduced the risk of HPV-related
cancers including cervical cancers carefully applying the healthy vaccinee effect.

As a result, we found that the HPV vaccines increased all cause and cancer mortality in mid-adultwomen from RCTs. We could not find any evidence of decreasing incidence of HPV-related cancer after

adjusting for the healthy vaccinee effect. Moreover HPV vaccination seems to increase anal cancer risk
in women vaccinated at the age 17 or older.

Guidelines or check lists for observational studies such as STROBE (strengthening the reporting ofobservational studies in epidemiology statement), NOS (Newcastle-Ottawa Scale) and MOOSE (Metaanalyses Of Observational Studies in Epidemiology) do not mention the necessity of considering thehealthy vaccinee effect. We believe it is high time to incorporate the healthy vaccinee effect for allobservational studies on the effectiveness and harm of vaccines.

Page 2 ・ MED CHECKMay. 2024/ Vol.10 No.29

Review

HPV vaccines increase total and cancer mortality
without evidence of HPV-related cancer decrease

Translated and revised from Med Check (in Japanese) May 2024 (P52-56)
MedCheck Editorial team

Abstract●Active recommendation of HPV vaccination was resumed from April 2022 in Japan after 9 year of its
suspension from June 2013 due to serious harm.
● The effectiveness of HPV vaccination on reducing the incidence of HPV-related cancer and the risk
especially on increasing cancer and total mortality are reviewed● Meta-analysis of two long-term randomized controlled trials (RCTs) of HPV vaccines in women aged
24 to 45 years showed that total mortality and cancer mortality were significantly increased by 5.0
times, and 7.4 times, respectively.
● If all Japanese women aged 25 to 44 years received HPV vaccine, annual total and cancer deaths
might increase as follows: compared with the annual cervical cancer deaths (516 in 2022), 24 times (atleast 10 times) more from all cause and 12 times (at least 4 times) more from any cancer.

● Although there are no RCTs showing that the HPV vaccine reduced the incidence of invasive cervicalcancer, we found five observational studies indicating apparent reduction of cervical (or HPV-related)cancer and one observational study showing an aparent reduction of anal cancer in women. However,these apparent protective effect disappeared after adjusting for the healthy vaccinee effect.
● Also, among women who received the HPV vaccine at the age of 17 or older, the incidence rate ofdeveloping anal cancer was significantly higher by 2.8 times, which is consistent with the results fromthe RCTs.
● As we have been reporting repeatedly, autoimmune diseases, cognitive disorders, and movement
disorders frequently occur in women after receiving the HPV vaccine. This review adds to the evidence
on increased cancer and all-cause mortality based on a meta-analysis of RCTs and observational studies.
Conclusions: HPV vaccines significantly increase cancer and all-cause mortality without evidenceof a reduction of HPV-related cancers. HPV vaccines should be withdrawn.

Keywords:
HPV vaccine, HPV-related cancer, HPV-unrelated cancer, all-cause mortality, cancer mortality, healthy vaccinee effect, autoimmune
disease, cognitive impairment.prior event rate ratio (PERR) adjustment method, cofounding bias

Introduction

the transition to routine vaccination in April 2013,
harmful reactions to HPV vaccines, such as serious

The HPV vaccine was launched in the United States

ne uro lo gi ca l di so rde r s we re re ve a le d, a nd ac t ive

in 2006 for the purpose of preventing cervical cancer

recommendation was withdrawn [4,5]. Nevertheless,[1]. In Japan HPV vaccination has started in 2009 within 2020 Gardasil was approved for use in males

Cervarix® (bivalent) [2], while Gardasil® (quadrivalent)[6]. I n addition, 9-valent HPV vaccine (Silgard®9)

was approved in 2011 [3]. However, immediately after

wa s l a u n c h e d i n J a p a n i n Fe b r u a r y 2 0 2 1 [ 7 ] , a n d
MED CHECKMay. 2024/ Vol.10 No.29 ・ Page 3

Review
active recommendation resumed in April 2022 [5,8]consequence of these results the HPV vaccination(Supplementary Appendix 1).

uptake of at least one dose has increased from less thanThe harms of the HPV vaccine have been repeatedly

1% during 2014 to 2018, to 37.4% in 2021, and to 42.2%

described in detail in MedCheck in English [9-12],

in 2022 [19] (which is still lower than the average of 75%

MedCheck (in Japanese), in Web MedCheck (in Japanese),during several years before the active recommendation

and The Informed Prescriber (in Japanese) . However,

was withdrawn[20]), and it may increase further in thes o m e e p i d e m i o l o gi c a l s t u d i e s re p o r te d t h at H P V

future. For this reason, we reviewed again the benefits

vaccination was apparently effective in preventing

and harms of the HPV vaccine.

i nv a s i v e H P V- r e l a t e d c a n c e r s [ 1 3 - 1 8 ] . Po s s i b l y i n

Figure 1: Sensitivity analysis of Analysis 7.7 on deaths restricting to data extracted from publications in peer-reviewed journals.
(Source: Figure 11, Cochrane’s systematic review and meta-analysis [21])Page 4 ・ MED CHECKMay. 2024/ Vol.10 No.29

RCTs show increased cancer and total mortality
1. Cochrane RCT review

The results showed that the odds of death was

As one of the most important sources of evidence

significantly higher without heterogeneity in HPV

for evaluating the efficacy and safety of drugs andvaccinated 24 to 45 year old women compared withv a c c i n e s, we e x a m i n e d t h e Co c h r a n e s y s t e m a t i c

those who received control agents (odds ratio=3.31, 95%

review and meta-analysis of HPV vaccines’ RCTs [21].

CI: 1.38 to 7.97, P=0.0082 and I2 =0%), while there was noA l t h o u g h t h e Co c h r a n e re v i e w re p o r t e d m u c hdata on HPV vaccine efficacy against cervicaldifference in mortality odds in younger women (Table 1
and Supplementary Appendix 2).

precancer (cer vical intraepithelial neoplasia grade 2

As the Cochrane review [21] contains some inaccuracies,

and above [CIN2+], CIN grade 3 and above [CIN3+], andwe independently extracted data from the publishedadenocarcinoma-in-situ [AIS]) , it did not repor t any

peer-reviewed papers including supplementar yevidence of efficac y against invasive HPV-related

appendix that Cochrane review cited and correctedcancer including cervical cancer.

data accordingly.

On the other hand, the data reported in the Cochrane

For example, Figure 11 in the Cochrane review

review [21] indicate potential harm signal with regards[21] (cited as Figure 1 in this report) is the sensitivity

to cancer and all cause mortality, as discussed below.

analysis of Analysis 7.7 on deaths restricting to

In the Cochrane review abstract, the authors stateddata extracted from publications in peer-reviewedthat they “did not find an increased risk of serious

journals. This figure shows that apparently one

adverse effects. Although the number of deaths is low

death was recorded in the HPV vaccine group in theoverall, there were more deaths among women older

Chinese trial of mid-adults [22]. However, Zhu et althan 25 years who received the vaccine. The deaths[22] reported “no event had a fatal outcome.” in thereported in the studies have been judged not to be

published paper with 12 months duration of followup.

related to the vaccine.”[21]Hence, we excluded the Chinese data [22] from theAs the mortality of women older than 25 years who

meta-analysis.

received the vaccine increased, we compared theOn the other hand, Cochrane review selected 13

proportion of death and odds ratios in the RCTs of HPVdeaths in the HPV vaccine group and 5 deaths in thevaccines by age group using Cochrane review’s data

control group during 84 months of follow-up of the(Table 1 and Supplementary Appendix 2).

VIVIANE trial [23], an RC T of Cer varix in mid-adult

Table 1: Proportion of death and odds ratios in the RCTs of HPV vaccines by age(from the data reported in the Cochrane’s systematic review and meta-analysis 2018 [21])Aluminium adjuvanted hepatitis A vaccine was administered as a control agent in most Cervarix trials except the Japanese trial and the Chinese trial in which a non adjuvanted
hepatitis A vaccine and an adjuvanted hepatitis B vaccine were used respectively as control agent. An alminium containing “placebo” containing Merck’s proprietary amorphousaluminium hydroxyphosphate sulphate (AAHS) adjuvant was used in all Gardasil trials (See details of the control agents on Supplementary Appendix 2

MED CHECKMay. 2024/ Vol.10 No.29 ・ Page 5

Review
Table 2: Death cases and their causes in the HPV vaccines’ RCTs in mid-adult women of 24 to 45 years of age

2) Cervix cancer metastatic: This woman had normal cytology but was HPV-18 DNA-positive at study entry (May 2006). At the next scheduled cytology testing at Month 12(April 2007), the cytology finding was atypical squamous cells cannot exclude high grade squamous intraepithelial lesion. She was diagnosed with metastatic cervical cancer in
May 2007 (approximately 7 months after receiving the third dose of vaccine or control) and died in July 2008 [23].
14)The woman not included in the M84 database was diagnosed with breast cancer 6 months after the third dose of the vaccine. Her death was not considered related to thevaccine. The woman did not enroll in the extension study and concluded the study at M48 (October 2010). She died in February 2011, 6 months after concluding the study. As
defined by the protocol, the breast cancer event should not have been followed up beyond M48, and therefore this death should not have been recorded in the database [23].

women. However, from the 4 years interim report [24]months database according to the protocol as per theand the 7 years final report [23], it is clear that there

authors’ explanation (Table 2) .

were 13 deaths in the vaccine group and 3 deathsin the control group reported during the 48 months

2. Cancer deaths occurred only in vaccine group

follow-up period. Moreover, there was one death inwithin 4 years

the vaccine group and 2 deaths in the control group

Table 2 shows the cause of death cases in HPVthat were reported during the extension 36 months

vaccines’ RCTs for mid-adult women. The numbers of

fo l l ow - u p p e r i o d u p to 8 4 m o n t h s. I n p a r t i c u l a r,

patients who died from malignancies within 4 years

one woman who was diagnosed with breast cancer

were five in the VIVIANE (Cervarix) trial [23,24] and three

6 months after the third dose of the vaccine did notin the FUTURE III (Gardasil) trial [25] both within 4 years,

enroll in the ex tention study and this 14th death

while no such cancer deaths were obser ved in thecase in the vaccine group was not recorded in the 84

control group of both trials within 4 years. During the

Figure 2:Total and cancer mortality risk during 4 years after HPV vaccination

HPV V: HPV vaccine group, Cont.: control group. *: aluminium adjuvant (see Supplementary Appendix 2 for details)
d: number of total deaths. Cd: number of cancer deaths.

Page 6 ・ MED CHECKMay. 2024/ Vol.10 No.29

Table 3: Risk difference of mortality rate and NNTH (*a) during 4 years after HPV vaccination*a: Number needed to treat to harm,*b: mortality rate (/100,000 person-years) ,pys: person-years, RD: Risk difference, 95%CI: 95% confidence interval

extension follow-up period, one patient in the HPV

a few years thereafter and again increased rapidly after

vaccine group and 2 in the control group of VIVIANE

five years or later of transplantation [26].

trial died from malignancies [23].
It should be noted that one patient died from cervicalcancer with metastasis. The origin of other malignancies

3. Reanalysis found robust increase in total andcancer mortality risk with HPV vaccine
We conducted meta-analysis on the total and cancer

varied such as breast (4) , lung, brain, bone marrow andnasopharynx in the HPV vaccine group [23,24].

mortality risk by various methods including odds ratio,

It is also noted that malignancies occurred more

Peto odds ratio in the case with zero event in at leastd u r i n g f i r s t 4 ye a r s a n d p o s s i b l y l e s s d u r i n g t h e

one arm, risk difference and number needed to treat tosubsequent 3 years, although acurate person-years

harm (NNTH) and their 95% confidence intervals (95%CI).

at risk during the latter period are not known. If thisFigure 2 shows the meta-analysis results of the odds

is true, it suggests that the progression of subclinicalratio for total mortality and the Peto odds ratio forcancer was promoted by the administration of HPVcancer mortality. Both total and cancer mortality risks

vaccine possibly by its immune suppressing property.

increased without heterogeneity. The pooled odds ratio

Very potent immunosuppressants such as calcineurin

was 5.00 (95%CI: 1.71, 14.65) for total mortality (P=0.0022,

inhibitors induced malignancies rapidly within one year

I2 =0%) and the poolded Peto odds ratio was 7.37 (95%CI:

after use in transplantation, while they induced less for

1.84, 29.50) for cancer mortality (P=0.0047, I2 =0%).

Table 4: Comparison of estimated increase in total or cancer deaths, and the number of cervical cancer deaths, assumingthat all women aged 25-44 in Japan received HPV vaccinea. NNTHs for total and cancer death are based on the Table 4. b. and d. are based on the ref. [26]

MED CHECKMay. 2024/ Vol.10 No.29 ・ Page 7

Review
Table 3 shows the risk difference in mortality rate
and the number needed to treat to harm (NNTH) for
total and cancer mortality during the 4 years after HPV
vaccination from two RCTs [23-25].

4. Increased total and cancer deaths may be far
more than cervical cancer deaths
Table 4 shows the comparison of the estimatedincrease in the number of total (Table 4A) and cancer

The authors of the Cochrane review stated that,deaths (Table 4B) , assuming that all women aged 25 to“Although the number of deaths is low overall“, and44 years in Japan [26] received HPV vaccine. Table 4 also

“The deaths reported in the studies have been judged

shows the number of cervical cancer deaths in 2022 in

not to be related to the vaccine”. However, more

Japan [26]. If the number of total deaths and of all cancer

than 90/100,000 person years (pys) of the statisticallydeaths were estimated by using the point estimate

significant risk difference for total mortality and nearlyof the NNTH, 24 times and 12 times more women at

50/100,000 pys of the statistically significant risk

the same age might die from any cause and from any

difference for cancer mortality are not low at all, andcancer respectively. If estimated by the upper limit ofcannot be simply dismissed as not related to the vaccine

the 95% confidence interval, at least 10 times and 4

on the basis of apparently subjective impression whichtimes more women of the same age might die from any

does not appear to be suppor ted by the statisticalcause and from any cancer respectively. These estimatesanalysis.

should not be ignored.

The pooled NNTH (95% CI) was 1072 (670, 2674)

This means that even if all cervical cancer deaths

for total mortality and 2132 (1259, 6944) for cancer

were prevented (actually, it’s impossible), at least 9 times

mortality. This means that if mid-adult women aged

more women might die from any cause and 3 times

24 to 45 years received the HPV vaccine, one in 1072

more women die from any cancer compared with themight die from any cause and one in 2132 might die

prevented deaths from cervical cancer. Therefore, thefrom any cancer every year during the first 4 years after

harm of HPV vaccine is definite.

vaccination.

Figure 3:Data claiming that vaccine reduced HPV-related invasive cancers*a：Because HPV vaccine is not effective in suppressing HPV-unrelated cancers, significantly low incidence rate ratio for HPV-unrelated cancers in the vaccinated groupcompared with that in the unvaccinated group (0.43) should be considered as healthy vaccinee effect.

Page 8 ・ MED CHECKMay. 2024/ Vol.10 No.29

Table 5: Incidence rate ratio of HPV-unrelated cancers indicate Healthy vaccinee effect:
After adjusting the healthy vaccinee effect, reported effectiveness on HPV-related invasive cancer prevention disappeare*a：Therefore, the number of HPV-related cancers in unvaccinated group (10) is multiplied by 0.43 to reach 4.3. Then the incidence rate of vaccinated group (0/65,656 pys)
and unvaccinated group (4.3/124,245 pys) were compared yielding no significance (P=0.306). See Supplementary Appendix 4-6 in details.

All Observational studies failed to provide evidence
for invasive cancer prevention
1. Review of six observational studies claiming beneficial

searched for data that could be used to adjust foreffect of HPV vaccines in reducing HPV-related cancers

healthy vaccinee effect.

To date, there have been at least five reports of large-

As a result, we found two data indicating healthy

scale obser vational studies claiming that the HPV

vaccinee effect. One in the FS1 [13] and the other in thevaccines reduced cervical cancer [13-17]. Additionally,

Scottish study [17].

there is one observational study that reported that

Because HPV vaccine does not reduce the incidence

the incidence of anal cancer, including high-gradeof HPV-unrelated cancers, the significant reductionsquamous intraepithelial lesion (HSIL), was significantlyin these cancers in the vaccinated would indicate

lower in women who received HPV vaccines than inthat unvaccinated individuals were ‘cancer-prone’ atnon-vaccinated women [18]. The characteristics of thesebaseline. The authors of the FS1 commented “Incidence

six studies are shown in the Supplementary Appendix

rates of other, non-HPV associated common cancers

3. Among them, the second Finnish study (FS2) [14]did not differ between the non-vaccinated and HPV

appears to be a follow-up study of the first Finnish study

vaccinated women.”(FS1) [13]. However, the vaccinated cohort in FS2 lost the

However, this obser vation is based on the non-vaccinated population from the cluster RCT subjects

significant difference in the incidence differences of[28] which accounted for almost two thirds of that in theindividual non-HPV-related cancers, such as breast

FS1 [13]. On the other hand, a new unvaccinated cohort

cancer, thyroid cancer, or melanoma, and not on HPV-

was added in the FS2, but this cohort received theunrelated cancers in total (Figure 3).

aluminium adjuvant from the FUTURE II trial [29]. TheseIn fact, the incidence rate ratio (IRR) of HPV-unrelated

procedures violate the principle of cohort study. Hence,cancers in total was significant: IRR = 0.43 (95%CI:

the suspicion that HPV-related cancers, such as cervical

0.20, 0.93, P=0.0277) (Figure 3, Table 5) . This figure (0.43)

cancer might have developed later in the cluster RCT

clealy indicates a healthy vaccinee effect (See also

subjects cannot be ruled out.

Supplementary Appendix 4 to 6 in detail).

In a Scottish study [17], the IRR of cervical cancer
2. Two papers provided data suggesting healthy

among those who had complete HPV vaccination

vaccinee effect on cancer incidencecompared with those who had incomplete HPV

It is important to note that none of the six observational
studies [13-18] adjusted for the healthy vaccinee effect:

vaccination was 0.36 (0.15, 0.85) (Supplementary Appendix
7-9).

i.e. health status prior to vaccination. Therefore, we

According to the Cochrane review [21], pooled risk

examined the data in references [13-19] in detail andratio of cervical lesion with CIN 3+ associated with HPVMED CHECKMay. 2024/ Vol.10 No.29 ・ Page 9

Table 6: Summary of original and healthy vaccinee effect adjusted incidence rate ratios for HPV-related cancers*a: When the number of cases in the vaccinated group was 0 (Finnish study [14,15] and 12-13 years in the Scottish study) [18], the incidence rate ratio (IRR) was calculated bymultiplying the total number of HPV-related cancer cases in the unvaccinated group by 0.43 and 0.36. The other IRRs or hazard ratios (HRs) were adjusted for healthyvaccinee effect by dividing 0.43 (95%CI) and 0.36 (95%CI) (See Table and Appendix 11-13).
*b: Original IRR and its 95%CI were calculated from the data for vaccine effectiveness data as described “Intention-to-treat vaccine efficacy against all HPV-positive cancers
was 100% (95%CI: 2 to 100, p<0.05).”*c: The lower limit of the 95%CI reported in the literature was 0.00, which precluded adjustment calculation. Therefore, instead of 0.00, we used 0.00499 which is the
maximum possible value with three significant digits.
*d: Upper limit of the 95% CI of IRR adjusted by 0.43 was lower than 1.0 but that by 0.36 was higher than 1.0. Note that the healthy vaccinee effect is maximized (IRR is thelowest as low as 0.10, 95%CI: 0.08, 0.13) in the age of 6 to 15 years according to De Wals et al.[29] (See the column of “About Healthy vaccinee effect as key confounding
bias in the observational study” in this issue). Hence 0.86 or 1.16 for the upper limits are is too low as adjusted IRR.
*e: Incidence rate ratios were calculated. using the unadjusted data for vaccine effectiveness (VE) on Table 2 of Ref [18], except *e and *f.
*f: Incidence rate ratios were calculated from the number of weighted person-years, which is the sum of incomplete vaccinee and complete vaccinee of all ages, and the number
of weighted observed events.
*g: Since the follow-up period for the 12–13-year-old group is essentially 5 years, the number of events in unvaccinated group during the 5-year follow-up period was read fromthe graph and estimated to be 34 (Appendix 18) to estimate the incidence rate ratio.
*h: High-grade Squamous Intraepithelial Lesion*i: It is suggested that HPV vaccination at the age of 17 to 32 years increased risk of developing anal cancer according to the data adjusted for healthy vaccinee effect.

16/18 was 0.07 (95%CI: 0.02, 0.27) for 3 doses and 0.06

o cc u r re n ce o f o u tco m e s a re c a l l e d “co n fo u n d i n g(0.01, 0.24) for 1 or 2 doses of HPV vaccine comparedf a c t o r s” [ 3 0 ] . I n o rd e r t o a vo i d t h e s e b i a s e s f ro mwith the control group. These data suggest that theconfounding various statistical methods have been

complete and incomplete vaccination do not differ indeveloped including standardization, multivariate

the reported effectiveness for suppressing sustained

analysis using Cox propor tional hazards model,

HPV infection with precancerous lesion. Hence thepropensity score matching method [30] and thesignificantly low IRR of the completely vaccinatedprior event rate ratio (PERR) adjustment method forcompared with the incompletely vaccinated may not“unmeasured confounding” proposed by Tannen et al [31].

be due to the full vaccination but due to the healthy

For calculation of IRR adjusted for healthy vaccinee

vaccinee effect. The level 0.36 as healthy vaccinee effecteffect, PERR adjustment method [31] was principallyin the Scottish study is not substantially different fromapplied by dividing 0.43 (95% CI) or 0.36 (95% CI) . 95%

0.43 obtained from the FS1.

confidence interval of PERR adjusted IRR was calculatedby the Kollassa’s method [32]. When the number of

3. Prior event rate ratio (PERR) adjustment method

cases in the vaccinated group was 0 (in the two Finnish

for “unmeasured confounding”.

studies [13,14] and those vaccinated at 12 to 13 years of age

I n a cohor t study, it is inevitable that baselinein the Scottish study [17]), the adjusted IRR was calculatedcharac teristics between both groups are different

by multiplying the total number of HPV-related cancer

leading to biased occurrence of events. Biased factors

cases in the unvaccinated group by 0.43 or 0.36.

w h i c h a f fe c t b o t h s e l e c t i o n o f i nte r ve nt i o n s a n dPage 10 ・ MED CHECKMay. 2024/ Vol.10 No.29

4. HPV vaccine effectiveness disappeared after

6. HPV-unrelated cancers increased rapidly

adjusting for the healthy vaccinee effectafter 7 years of more of vaccination

Table 6 shows the original and adjusted IRR or HR of

The FS2 [14] followed for an additional 3 years beyond

HPV vaccination for HPV-related cancers or for cervicalthe originally followed 7 years only the RCT subjects

cancer using 0.43 and 0.36 as the healthy vaccinee(extremely healthy HPV vaccinees), which is about one-effect. For the adjustment of data from the Scandinavian

thirds of the HPV vaccinated population in the FS1studies[13,14,18], 0.43 from FS I and for that from British[13], excluding the cluster RC T subjects (moderately

studies [16,17], 0.36 from Scottish study may be adequate

healthy HPV vaccinees), which accounted for almost two(see Supplementary Appendix 3 to 9 for detail).

thirds of vaccinated group of the FS1 [13]. Moreover,The upper limit of the 95% confidence interval for thethe aluminium adjuvant control population in the RCT

adjusted IRR or HR was greater than 1.0 in all studies“FUTURE II” (hence aluminium adjuvant toxicity could occur)(not statistically significant). Only one exception was those

was added as the control population in the FS2 [14], andvaccinated at 12 to 13 years of age in the England study

followed for an additional 3 years beyond the originally[16] by adjusting 0.43 from FS I [13]. However, it was

followed 8 years, and then the comparison was madegreater than 1.0 by adjusting 0.36 from the Scottish

between the vaccinated and unvaccinated groups.

study [17]. Moreover, it should be noted that the healthy

The 3-year period of this extended part of the study

vaccinee effect is maximized (IRR is the lowest at 0.10,

is designated as period 2, and the original period of

95%CI: 0.08, 0.13) at the age of 6 to 15 years according

the FS1 [13] is designated as period 1. The FS2 [14]to De Wals et al [33]. (See the column of “About Healthy

reported period 1 + 2.

vaccinee effect as key confounding bias in the observational

Incidence rates (IRs) of HPV-unrelated cancers instudy” on p 12-15 in this issue) . Hence 0.86 or 1.16 areperiod 1 and piriod 2 were calculated using the data

too low for the adjusted 95% upper limit of IRR.

from the FS1 [13] and the FS2 [14], and were compared

Cervical cancer was reportedly prevented by nearlyin order to find out whether the IR of HPV-unrelated

100% in girls vaccinated before the age of 17 years in acancer increased in period 2 compared with that in

Swedish study [15] and at ages 12 to 13 in the Englandperiod 1 in the vaccinated population.

and Scottish studies [16,17]. However, when these results

The results showed that the IR of HPV-unrelated

are adjusted (column E and F in the Table 6) , they are nocancers in period 2 compared with that in the period 1

longer statistically significant. Moreover, if the healthy

in the unvaccinated group increased 2.8-fold, which

vaccinee effect is greater (IRR is lower) than the values

may correspond to the increasing age. On the otherused (0.43 or 0.36), as suggested by the data in De Wals

hand, the IR of that in the vaccinated group increased

et al. [33], adjusted 95% upper limit of IRRs may be far

11-fold, which is disproportionately large (Supplementary

higher.

Appendix 5).

5. Anal cancer risk significantly increases when girls

HPV-unrelated cancers in the second period of theare vaccinated at age 17 or older

vaccinated group is related to the HPV vaccination.

I t canno t be e asily denied that the increase in

After adjusting for the healthy vaccinee bias,

Moreover, these findings correspond to the fact that in

vaccination in Danish women under the age of 17 did

the RCTs, cancer mortality increased 7-fold among 24 to

not reduce anal cancer (including high-grade squamous

45 year old women within 4 years.

intraepithelial lesion: HSIL) (Table 6) . What is even more

In addition, it should be noted that among womennoteworthy is that the incidence rate of anal cancer in

who received the HPV vaccine at the age of 17 or older,women after adjusting for the healthy vaccinee effectthe incidence rate of anal cancer (one of the HPV-related

was shown to be significantly increased when thecaners) after the adjustment for the healthy vaccinee

HPV vaccine was administered at ages 17 and older:effec was significantly higher by 2.8 times compared

IRR=2.80 (95%CI: 1.11, 7.04) adjusted by 0.43 and 3.40

with the unvaccinated (Table 6).

(95%CI: 1.24, 9.30) adjusted by 0.36.

MED CHECKMay. 2024/ Vol.10 No.29 ・ Page 11

Various adverse reactions to HPV vaccination may
contribute to the increase in total and cancer mortality
As we h ave b e e n re p e ate dl y re p or ti n g [4 , 8-12 ],prophylactic effectiveness of HPV-vaccine against HPV-

autoimmune diseases, cognitive and neurologicalrelated cancers based on the six observational studies,

disorders including movement disorders, frequently

disappeared after adjusting for the healthy vaccinee

occur in women after receiving the HPV vaccine. For

effect.

details on the harm of the HPV vaccine, please refer tothese publications [4,8-13].

Conclusion:

This review added the facts that cancer and all-cause

HPV vaccines significantly increase cancer andmortality risks increase based on the meta-analysis

total mortality risk without evidence for preventing

results of RCTs, and cancer risk increase based on the

HPV-related cancers. HPV vaccines should beobservational studies. It may be suggected that various

withdrawn.

adverse reactions after HPV vaccination contributed toReferences: see p15 - 16

the increased cancer risk and total mortality risk.
This review also added the fact that the apparent

ColumnHealthy vaccinee effect in observational studies
What is healthy vaccinee effect?
Sick people who have a fever due to infection or severe
illness tend to avoid vaccinations, while healthy people

theoretical basis [1,2], reviews [3,4] and on various vaccines[5-10] including DPT vaccine [2], influenza vaccine [4-9],
meningococcal vaccine [10], HPV vaccine [1, 11,12] and SARSCoV-2 vaccines [13-19].

receive them. Therefore, unvaccinated individuals are more

For example, Jackson et al [5] found the greatest

susceptible to various diseases, especially immune-related

reductions in the risk of death and of pneumonia

diseases such as infections and cancers (malignant tumors),

hospitalization in the period before influenza season,and have a higher risk of death than vaccinated individuals.

when there should be no true influenza vaccine effect.

Consequently, because the population opting for

Therefore, these risk reductions before influenza season

vaccination is generally healthier than the population

indicate preferential receipt of vaccine by relatively healthy

opting out of vaccination, even if the vaccine has noseniors. Jackson et al. also emphasized that adjustment for

efficacy or harmful effect, the risk and benefit analysis

diagnosis code variables did not control this bias [5].

would show that it is effective and safe. This is called

This bias is a sort of “unmeasured confounding” in“healthy vaccinee effect” and more generraly “healthy user

observational studies [5]. Tannen et al proposed to adjust itbias”. It is also called “frailty exclusion bias”[1].

by the prior event rate ratio (PERR) adjustment method [20].
Healthy vaccinee effect works in the direction ofWhat is known about Healthy vaccinee effectand points to be noted in this review

underestimating vaccine harm and overestimating vaccine

There is a substantial number of studies that show

it may be rational to take the healthy vaccinee effect into

evidence for the healthy vaccinee effect, including on

account in all observational studies that study both benefits

Page 12 ・ MED CHECKMay. 2024/ Vol.10 No.29

effectiveness universally in observational studies[1]. Hence,.

Figure 1:Theoretical influence of Healthy vaccinee effect by vaccine coverage and by various excludion rate

Modified From MedCheck in English 2016: 2 (No5): 18-21, Figure 3 and 4 [2]. See text for explanation.

and harms of any vacine.

By combining the Figure 1A and Figure 1B, suppose a vaccine

There are several reports on the relation between thehas no efficacy and no harm, and unless “e” is zero, odds ofdegree of healthy vaccinee effect and vaccination coveragefrailty before vaccination for the vaccinated compared with[1], severity of disease outcomes [5,8,13], observed periods

the unvaccinated becomes less than 1.0 (Columun Figure 1C). If[2,7,10,13], age at vaccination [10], and cause of death [10].

e=0.5, odds ratio of frailty of the vaccinated compared withthe unvaccinated is calculated as less than 0.5, even if the1) Vaccination coverage [2] (Column Figure 1)

coverage is low (15%). If the coverage increases up to 90%,

The greater the coverage, the greater the healthy

odds ratio decreases to less than 0.1. The spurious odds ratio

vaccinee effect (the smaller the incidence rate ratio/odds ratio/“0.1” may be erroneously conceived in extreme favour of thehazard ratio) [1].

vaccine, even if it has neither beneficial nor harmful effects at all.

If a vaccine has no efficacy and no harm and frailty is

This is the theoretical basis to explain that exclusion of

excluded by the proportion of “e” from vaccination andfrailty leads to overestimation of efficacy and underestimation

the proportion of frailty is less than 0.01, the proportionof harm of any vaccine [1].

of frailty decreases in the vaccinated population byapproximately (1-e) (Columun Figure 1A) . Vaccination
coverage does not affect the proportion of frailty in thevaccinated population

2) Severity of disease outcomes
As for the severity of disease outcomes after vaccination
including, asymptomatic infection, infection with clinicalIn the unvaccinated, the odds ratio of frailty at the start

symptomes, with hospitalization or death, the severer theof vaccination (after excluded) versus before vaccinationdisease outocome, the greater the healthy vaccinee effect(before excluded) increases greatly at the vaccine coverage[5,8,13]: Mortality risk ratio (outcome of death) shows theof 70% or over. (Column Figure 1B). If the vaccine coverage

greatest healthy vaccinee effect [13] (Column Figure 2A, seeis 15% (odds=0.18), influence of exclusion, i.e. odds ratio of

Supplementary Appendix for detailed explanation for the Figure 2):

frailty (after exclusion/before exclusion) in the unvaccinatedgroup is small under any proportion excluded (e). However,3) Observed periods after vaccination

if the coverage increases up to 90% (odds =9), the influence

The shorter the observation period after vaccination, thebecomes extreme: OR increases up to 5.5, under thegreater the healthy vaccinee effect [2,7,10,13]: Mortality

condition that one half of the frail were excluded (e=0.5).

risk ratio (MRR) or incidence rate ratio (IRR) at the day of
MED CHECKMay. 2024/ Vol.10 No.29 ・ Page 13

the vaccination shows the greatest healthy vaccinee effectfor all ages may underestimate the healthy vaccine effect(Column Figure 2B)[10].

when adjusting the incidence rate ratio for 12 to 13 years, orIncidence rate ratio at the day of vaccination or during

younger than 17 years of age.

very short period after vaccination may be used as aproxy of a prior event rate ratio. The extent of the healthy5) Causes of death:vaccinee effect on death were estimated best by the

Mortality rate ratio for natural causes or cause specificmortality risk at immediately after vaccination [2,7,10,13].

deaths such as cancer (makignant tumors) , respiratory

However, in this review, incidence rate ratios that we

disease, neurological disease, infection and so on areused as the proxy of the healthy vaccinee effect werecompared using the data from De Wals et al.[10] (Column

based on the studies with very long period of follow-up:

Figure 2D).

more than 6 years in average for both 0.43 and 0.36.

Cancer death shows the greatest healthy vaccinee effectcompared with other causes of death: Mortality rate ratio4) Age at vaccination (Column Figure 2C)[10].

was as low as 0.04 (95%CI: 0.03, 0.06).

Vaccination at 6 to 15 years of age show the greatest

What we have been discussing in this review is exactly

healthy vaccinee effect and less effect at the age younger

the effect on cancer, so the fact that healthy vaccinee

than 6 years or older than 15 years (Column Figure 2C).

effect is the greatest on cancer mortality is extremely

According to De Wals et al.[10], the MRR is 0.27 for thoseimportant and 0.43 or 0.36 used in this review as the proxyaged 15 years and older and 0.10 for those aged 6-15 years.

of the healthy vaccinee effect for adjustment may lead toConsidering these data, 0.43 to 0.36 used as the proxy ofunderestimation of this effect.

healthy vaccinee effect which were the IRRs calculated

Figure 2:Healthy vaccinee effect by factor
A. By severity of diseases outcomes

B. By length of follow-up

C. By age at vaccination

D. By cause of deathSee text and Supplementary Appendix for the explanation of Column 2 A to D

Page 14 ・ MED CHECKMay. 2024/ Vol.10 No.29

References for the column
1)MedCheck Editorial team. Symptoms after HPV vaccine: typical “frailty exclusionbias” in Nagoya study. MedCheck in English. 2016: 2(No 5): 18-21.
https://www.npojip.org/english/MedCheck/Med%20Check-TIP%2005-08-08.pdf
2) Fine, PE. & Chen, RT. Confounding in studies of adverse reactions to vaccines.
Am J Epidemiol 1992:136,121-135 .
3) Simonsen,L et al. Influenza vaccination and mortality benefits: new insights, newopportunities. Vaccine 2009: 27, 6300-6304 https://doi.org/10.101: 6/
j.vaccine.2009.07.008.
4) Remschmidt C et al, Frequency and impact of confounding by indication and healthyvaccinee bias in observational studies assessing influenza vaccine effectiveness: asystematic review. BMC Infect Dis 2015:15, 429 https://doi.org/10.1186/s12879-0151154-y.
5) Jackson LA, Jackson ML JC et al. Evidence of bias in estimates of influenza vaccine
effectiveness in seniors. Int. J. Epidemiol. 2006:35, 337-344 https://doi:10.1093/ije/
dyi2746) Hottes TS et al. Influenza vaccine effectiveness in the elderly based on administrative
databases: change in immunization habit as a marker for bias. PLoS. One. 2011: 6,
e22618 https://doi.org/10.1371/journal.pone.0022618
7) McCarthy NL et al. Mortality rates and cause-of-death patterns in a vaccinatedpopulation. Am. J. Prev. Med. 2013:45, 91-97. https://doi.org/10.1016/
j.amepre.2013.02.020.
8) McGrath LJ. et al. Influenza vaccine effectiveness in patients on hemodialysis: an analysis
of a natural experiment. Arch. Intern. Med. 2012: 172, 548-554
https://doi.org/10.1001/archinternmed.2011.2238.
9). Hosseini-Moghaddam SM, et al. Association of Influenza Vaccination With SARS-CoV-2
Infection and Associated Hospitalization and Mortality Among Patients Aged 66 Years or Older.
JAMA Netw Open 2022: 5, e2233730 https://doi.org/10.1001/jamanetworkopen.2022.33730.
10). De Wals P. et al. Analysis of mortality following a mass immunization campaign with11) MedCheck Editorial team. Harm of HPV vaccine: Latest information and examinationof epidemiological studies. MedCheck in English. 2015: 1 (No.1):9-14.
https://www.npojip.org/english/MedCheck/Med%20Check-TIP%2001-4-25.pdf12) MedCheck editorial team. Resuming HPV vaccination is dangerous. MedCheck in
English 2022: 8(No23): 3-10.
https://www.npojip.org/english/MedCheck/Med%20Check%20TIp-23-2022-04.pdf13) MedCheck editorial team. To Be Vaccinated or Not? Points You should Know-SARSCoV-2 Vaccines Doubles the Risk of COVID-19! MedCheck in English 2022; 8 (25): 40-52.
https://www.npojip.org/english/MedCheck/Med%20Check%20Tip-25-2023-02.pdf
14) Hama R, Watanabe S. The risk of vaccination may be higher by considering “healthyvaccinee effect” 27 Sept. 2022 Rapid response to Husby et al. SARS-CoV-2 vaccinationand myocarditis or myopericarditis: population based cohort study:
https://www.bmj.com/content/375/bmj-2021-068665/rr-515) Watanabe S, Hama R. SARS-CoV-2 vaccine and increased myocarditis mortality risk:
A population based comparative study in Japan.
medRxiv preprint doi: https://doi.org/10.1101/2022.10.13.22281036 (October 18, 2022)
16) Høeg TB, Duriseti R, Prasad V. Potential “Healthy Vaccinee Bias” in a Study of
BNT162b2 Vaccine against Covid-19. N. Engl. J. Med. 2023: 389, 284-285.
https://doi.org/10.1056/NEJMc2306683.
17) Fürst T, Bazalová A, Fryčák T et al. Does the healthy vaccinee bias rule them all?
Association of COVID-19 vaccination status and all-cause mortality from an analysis ofdata from 2.2 million individual health records. Int J Infect Dis. 2024 May;142:106976.
doi: 10.1016/j.ijid.2024.02.019. PMID: 38401782
18) Furst T, Straka R, Janosek J. Healthy vaccinee effect: a bias not to be forgotten inobservational studies on COVID-19 vaccine effectiveness. Pol Arch Intern Med. 2024;
134(2):16634. doi: 10.20452/pamw.16634. PMID: 38415516
19) Zagożdżon P. Bias in data analysis of the study “Effectiveness of the BNT162b2 vaccine
in preventing COVID-19-associated deaths in Poland”. Pol Arch Intern Med. 2023; 133: 16573
doi:10.20452/pamw.16573 PMID: 37772714
20)Tannen RL, Weiner MG, Xie D. Use of primary care electronic medical record databaseserogroup C meningococcal conjugate vaccine: methodological difficulties and mperfectin drug efficacy research on cardiovascular outcomes: comparison of database andsolutions. Vaccine 2009: 27, 3223-3227 https://doi.org/10.1016/j.vaccine.2009.02.055

randomised controlled trial findings. BMJ 2009: 338, b81 https://doi:10.1136/bmj. b81)

References for the main text of the review (P3 - 12)1) Gardasil package inserta) Gardasil package insert 2011(US) :https://www.fda.gov/files/vaccines,%20blood%20&%20biologics/published/Package-Insert-Gardasil.pdfb) Gardasil 9:https://www.fda.gov/media/90064/download
2) Cervarix: Package insert (in Japan), review by PMDA
https://www.pmda.go.jp/drugs/2009/P200900052/34027800_22100AMX02268_A100_1.
pdf3) Gardasil: Packageninsert (in Japan), review by PMDA
https://www.pmda.go.jp/drugs/2011/P201100122/170050000_22300AMX00600000_A100_2.pdf
4) MedCheck editorial team. Resuming HPV vaccination is dangerous. MedCheck in English
2022: 8(No23): 3-10.
https://www.npojip.org/english/MedCheck/Med%20Check%20TIp-23-2022-04.pdf
5) Japanese Ministry of Health, Labour and Welfare: Q&A of HPV vaccine.
https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/kenkou/hpv_qa.html#Q6-1
6) Gardasil: review by PMDA（2020/12/25）
https://www.pmda.go.jp/drugs/2020/P20201224002/170050000_22300AMX00601_A100_1.
pdf7) Silgard: Package insert, review by PMDA
https://medical.nikkeibp.co.jp/leaf/mem/pub/hotnews/int/202308/580798.html?n_cid=nbpnmo_mled_html-new-arrivals
8) MedCheck editorial team.Resuming HPV vaccination is very dangerous.Web MedCheck
No199（2021/12/30）https://www.npojip.org/sokuho/211230.html

by Jørgensen et al: https://ebm.bmj.com/content/ebmed/23/5/165.full.pdf
https://ebm.bmj.com/content/23/5/165.responses#cochrane-review-should-be-revised-due-to-overlooked-trials-toxicity-ofadjuvant-mortality-in-mid-adult-women-and-lack-of-discussion-on-observational-studies-with-serious-healthy-vaccinee-effect12) Hama R. Cochrane review should be revised: Due to missing trials, adjuvant toxicity, mortality
and healthy user bias in observational studies MedCheck in English 2022: 8(No23): 41-49.
https://www.npojip.org/english/MedCheck/Med%20Check-TIP%2012-12-18.pdf
13) Luostarien T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associatedcancers. Int J. Cancer 2018;142:2186-2187. PMID: 29280138
14) Lehtinen M, Lagheden C, Luostarinen T et al. Human papillomavirus vaccine efficacy against
invasive, HPV-positive cancers: population-based follow-up of a cluster-randomised trial.
BMJ Open. 2021 Dec 30;11(12):e050669. doi: 10.1136/bmjopen-2021-050669.PMID: 35149535
15) Lei J, Ploner A, Elfstr?m KM, et al. HPV Vaccination and the Risk of Invasive Cervical Cancer.
N Engl J Med. 2020 Oct 1;383(14):1340-1348. PMID: 32997908
16) Falcaro M, Castañon A, Ndlela B et al. The effects of the national HPV vaccination
programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial
neoplasia incidence: a register-based observational study. Lancet. 2021 Dec
4;398(10316):2084-2092. PMID: 34741816
17) Palmer TJ, Kavanagh K, Cuschieri K et al. Invasive cervical cancer incidence following
bivalent human papillomavirus vaccination: a population-based observational study ofage at immunization, dose, and deprivation. J Natl Cancer Inst. 2024 Jan 22:djad263.
doi: 10.1093/jnci/djad263. Online ahead of print.PMID: 38247547
18) Baandrup L, Maltesen T, Dehlendorff C et al. Human papillomavirus vaccination andanal high-grade precancerous lesions and cancer-a real-world effectiveness study. J Natl9) MedCheck Editorial team. Harm of HPV vaccine: Latest information and examination ofCancer Inst. 2024 Feb 8;116(2):283-287. doi: 10.1093/jnci/djad189.PMID: 37718496

epidemiological studies. MedCheck in English. 2015: 1 (No.1):9-14. https://www.npojip.

19) MHLW’s documents (a) https://www.mhlw.go.jp/content/10601000/001197476.pdf

org/english/MedCheck/Med%20Check-TIP%2001-4-25.pdf10) MedCheck Editorial team. Symptoms after HPV vaccine: typical “frailty exclusion bias”
in Nagoya study. MedCheck in English. 2016: 2(No 5): 18-21. https://www.npojip.org/
english/MedCheck/Med%20Check-TIP%2005-08-08.pdf
11) Hama R. Cochrane review should be revised due to overlooked trials, toxicity of(b) https://www.mhlw.go.jp/content/10601000/001197476.pdf20) Nakagawa S, Ueda Y, Yagi A. et al. Corrected human papillomavirus vaccination rates
for each birth fiscal year in Japan. Cancer Sci. 2020 Jun;111(6):2156-2162.
doi: 10.1111/cas.14406. Epub 2020 Apr 27. PMID: 32248632
21) Arbyn_M, Xu_L, Simoens_C, Martin-Hirsch_PPL. Prophylactic vaccination against

adjuvant, mortality in mid-adult women and lack of discussion on observational studies

human papillomaviruses to prevent cervical cancer and its precursors.

with serious healthy vaccinee effect. Rapid response (on 8. Sept. 2018) to “TheCochrane Database of Systematic Reviews 2018, Issue 5. Art. No.: CD009069. DOI:

Cochrane HPV vaccine review was incomplete and ignored important evidence of bias”

10.1002/14651858.CD009069.pub3.

MED CHECKMay. 2024/ Vol.10 No.29 ・ Page 1522) Zhu_F, Li_J, Hu_Y, Zhang_X, Yang_X, Zhao_H, et al. Immunogenicity and safety of
the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese girls and women aged 9 to
45 years. Human Vaccines & Immunotherapeutics 2014;10(7):1795-806. doi: 10.4161/
hv.28702.PMID: 25424785

28) Lehtinen M, Apter D, Baussano I, et al. Characteristics of a cluster-randomized phase IV
human papillomavirus vaccination effectiveness trial. Vaccine 2015;33:1284–90. doi:
10.1016/j.vaccine.2014.12.019. PMID: 25593103
29) Lehtinen M, Apter D, Dubin G, et al.. Enrolment of 22,000 adolescent women to23) Wheeler CM, Skinner SR, Del Rosario-Raymundo MR, Garland SM, Chatterjee A,
Lazcano-Ponce E, et al. Efficacy, safety, and immunogenicity of the human papillomavirus
16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of thephase 3, doubleblind, randomised controlled VIVIANE study. Lancet Infectious
Diseases 2016;16(10):1154-68.

cancer registry follow-up for long-termhuman papillomavirus vaccine efficacy: guarding
against Guessing. Int J STD AIDS 2006;17:517–21. doi: 10.1258/095646206778145550
PMID: 16925896
30) Rothman KJ, Greenland S and Lash TL. Validity in Epidemiologic Studies. In Rothman KJ,
Greenland S and Lash TL eds Modern Epidemiology 3rd ed. Philadelphia: Wolters Kluwer/24) Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E, Salmeron J.
Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-

Lippincott Williams & Wilkins, 200831) Tannen RL, Weiner MG, & Xie D. Use of primary care electronic medical record databaseadjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3,

in drug efficacy research on cardiovascular outcomes: comparison of database anddouble-blind, randomised controlled VIVIANE study. Lancet 2014;384(9961): 2213–27.

randomised controlled trial findings. BMJ 2009: 338, Jan 27. b81. https://doi:10.1136/bmj.

25) Castellsagué X, Munoz N, Pitisuttithum P, Ferris D, Monsonego J, Ault K. End-of-study
safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinantvaccine in adult women 24 to 45 years of age. British Journal of Cancer 2011;105(1):28–37.
26) Roussel JC, Baron O, J Perigaud C et al. Outcome of heart transplants 15 to 20 years

b81. PMID:19174434
32) Kolassa S. Calculate 95% CI for ratio of odds ratio.
https://stats.stackexchange.com/questions/471805/calculate-95-ci-for-ratio-of-odds-ratio33) De Wals, P. Deceuninck G, Ouakki M et al. Analysis of mortality following a massago: graft survival, post-transplant morbidity, and risk factors for mortality. J Heart Lung

immunization campaign with serogroup C meningococcal conjugate vaccine:Transplant. 2008 May;27(5):486-93. doi: 10.1016/j.healun.2008.01.019. PMID: 18442713

methodological difficulties and imperfect solutions. Vaccine 2009: 27, 3223-3227 https://27) Vital statistics in “e-Stat: Statistics of Japan”

doi.org/10.1016/j.vaccine.2009.02.055 PMID: 19446195

https://www.e-stat.go.jp/en/stat-search/files?page=1&toukei=00450011&tst
at=000001028897

M
C

ED

2024

Vol.10

No.29

HECK

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD)Managing Editor: SAKAGUCHI, KeikoE d i t o r i a l S t a f f : N A K A N I S H I ,Ta ke a k i ( P h a r m a c i s t ) ; TA K A N O,
Yo s h i h i ko ( M D [ p e d i a t r i c i a n ] / P h a r m a c i s t ) ; U M E DA , Ta d a h i t o(MD[psychiatrist]) ; WATANABE,Sintaroo (MD); YANAGI, Motokazu (MD);YASUDA, Yoshinobu (Pharmacist)

Page 16 ・ MED CHECKMay. 2024/ Vol.10 No.29

Translators: NAKAMURA, Akari
Advisors:HONZAWA,Tatsuo (MD[GP]) ; IKEDA,Akiko (Pharmacist) ;KIM,Mieko (Pharmacist) ; KUDO,Shino (Pharmacist) ; MITA,Yasuko(Pharmacist) ; MUKAI, Junji (Pharmacist) ; SUMIDA, Sachie (MD[Dermatologist]); TERAOKA, Akio (Pharmacist) ; TOI, Chihiro (Pharmacist);
WADA,Masahide (MD[GP])Editorial Officer: SAKAGUCHI, Keiko
Production Team: UMEKI, Yukiko; SAKAGUCHI, Keiko; MATSUMOTO,
Koji
Information Technology (IT): KURODA, Akira (Systems Engineer)
Copyright JIP
http://medcheckjp.org
Registered address:#602, Katsuyama 2-14-8, Tennouji-ku,
Osaka JAPAN 543-0043