A Critical Look at the Japanese 23-Valent Pneumococcal Vaccine Randomized Control Trial

A Critical Look at the Japanese 23-Valent Pneumococcal Vaccine Randomized Control Trial

It’s not often that you find a published double blind placebo randomized control trial in the world of vaccine science, but when you do, you can bet your big-pharma stock that it will be tirelessly showcased in every newspaper, medical journal and vaccine apologist highlight reel until it finds its proper home in the archives of vaccine public policy. And with all the expected fanfare and pomp afforded to such occasions, the 2010 Japanese study titled, “Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomized and placebo controlled trial” proved to be no different.

The Study

The study of 1006 nursing home residents purports to show that “the 23-valent pneumococcal polysaccharide vaccine significantly prevented pneumococcal pneumonia and reduced the death rate from pneumococcal pneumonia in nursing home residents”. In their abstract, the authors (Maruyama et al.) state that death from pneumococcal pneumonia was significantly higher in the placebo group than in the vaccine group, with 13 deaths in the placebo group compared to no deaths in the PPV23 group. The study also reports a vaccine efficacy (VE) of 65% for pneumococcal pneumonia and 45% for all cause pneumonia. Since being published in 2010, this study has been incorporated into global vaccine policy and recommendation guidelines, despite very real concerns with the validity and reliability of its claims.

Study Inconsistencies and All Cause Mortality

A review of the study published in Science Direct in August of this year highlights serious issues with both internal and external inconsistencies and calls into question its validity altogether. In a graph outlined in their review, the authors (Gessner et al.) point out that using even unrealistically high controls, they could not surpass a PPV23 vaccine efficacy of 19.5%, despite the study reporting a PPV23 VE of 45%; they also claim that a 50% all cause pneumonia reduction was similarly statistically improbable.

Additionally, in a published response to the Maruyama et al claim that the PPV23 vaccine had a positive impact on group mortality, Dr. Motoi Suzuki, an epidemiologist with the Institute of Tropical Medicine at Nagasaki University, expressed his concern that the PPV23 actually increased all cause mortality, “We recalculated the efficacy of PPV23 against mortality during the follow up period (mean 2.28 years) and found that… it increased the mortality related to other causes by 41% (95% CI: 2% to 96%). It indicates that for each year, 89 older people need to be vaccinated to prevent one death from pneumonia but that for every 52 older people vaccinated there is one extra death from a condition unrelated to pneumonia.” 3 Summarizing his concerns over the substantial impact the study had already had on global public health policy, Dr. Suzuki urged the authors to make their complete study data publicly available for examination.

Despite expressly denying that the PPV23 had any direct correlation to an increase in all cause mortality as seen in the vaccine group, Maruyama et al refused to publish their study data, opting instead to publish a supplemental table 5 detailing the causes of death in the study population during following the initial 28 day post vaccination surveillance period. Review of this data, which compared all cause mortality in the PPV23 vaccine group to the placebo group, was nothing short of startling. In all, there were 88 deaths recorded in the PPV23 group during the 2.23 year follow up period, 13 of which were related to pneumonia, compared to 77 deaths in the placebo group, 25 reportedly due to pneumonia. Additionally, the PPV23 group saw 5 deaths from cancer, 4 deaths from organ failure, 3 deaths from necrotizing fasciitis, 3 deaths from gastrointestinal hemorrhage and 2 deaths from pulmonary tuberculosis, while the vaccine group saw only one death each from organ failure and gastrointestinal hemorrhage and recorded zero deaths from any of the other above mentioned categories. Perhaps the most notable difference between the vaccine and placebo groups was in the category of senility; the placebo group recorded a total of 23 senile related deaths while the PPV23 vaccine group recorded 33. 5 Taking into account the fact that the study methods were designed to exclude existing cases of cancer and senility from the study population, these results are enough to give rise to questions concerning the effect of PPV23 vaccination on non-pneumococcal mortality, despite the assurances of Maruyama et al. While the compromised systemic condition of the study population could account for the overall post-vaccination mortality numbers as a whole, it does not address the obvious variances between the two groups.

Vaccine Efficacy and Immunological Memory

The question of PPV23 vaccine efficacy was also raised in published responses to the Maruyama et al. study. In an editorial titled, “Invasive Pneumococcal Disease in Adults Previously Vaccinated with 23-valent Pneumococcal Polysaccharide Vaccine, authors Fay et al. summarize a retrospective audit of patients with invasive pneumococcal disease (IPD) admitted to a District General Hospital in England, that, “contrary to Marayuma’s work, suggest vaccine failure of the 23-valent PPV in preventing invasive pneumococcal disease (IPD).” Gay et al. continue, “Prior to conducting this audit we perceived that the majority of patients admitted with proven pneumococcal disease would not have been vaccinated. Results surprisingly demonstrated that, despite being vaccinated, many patients were not sufficiently protected against serotypes contained within the 23-valent vaccine and subsequently had proven pneumococcal infection. In contrast to the work of Marayuma et al, our study concludes that the efficacy of 23-valent PPV was suboptimal. Unlike conjugate vaccines, it is well recognized that polysaccharide vaccines do not promote immunological memory or provide long-lasting protection.” 6

Immunological memory is defined as the ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a corresponding immune response. As mentioned above, several studies have demonstrated the inability of polysaccharide vaccines to promote immunological memory 7-11; ideally, the effect of vaccination is to elicit immunological memory, and thus resistance to the specific pathogen contained within the vaccine. In an article titled Pneumococcal Vaccination in High-Risk Individuals: Are We Doing It Right?, authors Papadatou et al. examines the controversy regarding the optimal use of the 23-valent PPV for protection of high-risk individuals, citing the failure of the vaccine to produce immunological memory and long term protection and new concerns that polysaccharide vaccines may actually increase IPD susceptibility in high risk populations, “Interestingly, there are findings implying not only attenuated protection but possibly an increased risk for IPD in individuals with severe immunodeficiency induced by the use of polysaccharide vaccines. Increased rates of all-cause pneumonia have been demonstrated among HIV-infected PPV23 recipients in Uganda compared to unvaccinated patients.” 12

Replication Crisis

Despite its elevation as the gold standard of randomized controlled trials and its considerable impact on global vaccination policy, we were unable to find a single scientific study or review that supported the outcomes of Maruyama et al. On the contrary, Papadatou et al. conclude that current immunization guidelines do not take into consideration the hyporesponsiveness of the PPV23, and call for immunization protocol to be revised accordingly 12. Gessner et al., after utilizing the Cochrane Collaboration’s tool for assessing risk of bias in randomized trials, identified several gaps in reporting that could reflect deficiencies that could have led to study bias and go on to question whether randomization was properly maintained.2 In a systematic review and meta analysis of the efficacy of PPV23 in preventing pneumococcal pneumonia in adult populations, Schiffner-Rohe, authors Julia, et al dismiss the Maruyama study as a scientific outlier, concluding, “ To date there is no proof that PPV23 can prevent pneumonia in a general, community-dwelling elderly population.” 16

Despite overwhelming scientific consensus refuting the efficacy of the PPV23 vaccine in preventing pneumococcal pneumonia, national and global health entities continue to rationalize its inclusion in public health policy by citing the Maruyama et al. study 17-23, further alienating themselves from their intended goal of maximizing and protecting public health. We echo the sentiments of Gessner et al., who concluded their review of the Maruyama study with this bold statement, “we think the issues we raise here are serious enough that when national decision-makers globally are weighing the benefits of different pneumococcal vaccines in the general adult population, the Maruyama study should be considered an outlier whose relevance – if any – should be limited to the unique population in which the study was conducted 2.”

References

1. T. Maruyama, O. Taguchi, M.S. Niederman, et al. “Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and placebo controlled trial.”

2. Gessner, Bradford D., et al. “Rethinking results from the Japanese 23-valent pneumococcal polysaccharide vaccine randomized clinical trial.”

3. Suzuki, Motoi, et al. “Concerns about the PPV23 Trial in Japan.”

4. Gabazza, Esteban Cesar, and Takaya Maruyama. “Mortality Unrelated to Vaccine during Long-Term Follow-Up.”

5. Gabazza, Esteban Cesar, and Takaya Maruyama. “Mortality Unrelated to Vaccine during Long-Term Follow-Up.”

6. Fay, Karen M, and Cecilia M Jukka. “Invasive Pneumococcal Disease in Adults Previously Vaccinated with 23-Valent Pneumococcal Polysaccharide Vaccine.”

7. Poolman J, Borrow R . 2011. “Hyporesponsiveness and its clinical implications after vaccination with polysaccharide or glycoconjugate vaccines.”

8. Davies JM, Lewis MPN, Wimperis J, Rafi I, Ladhani S, Bolton-Maggs PHB. Review of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen: prepared on behalf of the British Committee for Standards in Haematology by a Working Party of the Haemato-Oncology Task Force.

9. Granoff DM, Gupta RK, Belshe RB, Anderson EL . 1998. “Induction of immunologic refractoriness in adults by meningococcal C polysaccharide vaccination.”

10. Sigurdardottir ST, Center KJ, Davidsdottir K, Arason VA, Hjalmarsson B, Elisdottir R, Ingolfsdottir G, Northington R, Scott DA, Jonsdottir I. “Decreased immune response to pneumococcal conjugate vaccine after 23-valent pneumococcal polysaccharide vaccine in children.”

11. Russell FM, Carapetis JR, Balloch A, Licciardi PV, Jenney AW, Tikoduadua L, Waqatakirewa L, Pryor J, Nelson J, Byrnes GB, Cheung YB, Tang ML, MulhollandEK . “Hyporesponsiveness to re-challenge dose following pneumococcal polysaccharide vaccine at 12 months of age, a randomized controlled trial.”

12. Papadatou, Ioanna, and Vana Spoulou. “Pneumococcal Vaccination in High-Risk Individuals: Are We Doing It Right?”

13. French N, Nakiyingi J, Carpenter LM, Lugada E, Watera C, Moi K, Moore M, Antvelink D, Mulder D, Janoff EN, Whitworth J, Gilks CF. “23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised and placebo controlled trial.”

14. Understanding Science, University of Berkeley, “Copycats in Science: The Role of Replication.”

15. Wikipedia, Wikimedia Foundation. “Replication Crisis.”

16. Schiffner-Rohe, Julia, et al. “Efficacy of PPV23 in Preventing Pneumococcal Pneumonia in Adults at Increased Risk – A Systematic Review and Meta-Analysis.”

17. Australas J Ageing. “Australian and New Zealand society for geriatric medicine position statement-immunisation of older people.”

18. M. Woodhead, F. Blasi, S. Ewig, et al. “Guidelines for the management of adult lower respiratory tract infections–summary.”

19. M. Woodhead, F. Blasi, S. Ewig, et al. “Guidelines for the management of adult lower respiratory tract infections–full version.”

20. A.A. El-Solh, M.S. Niederman, P. Drinka. “Management of pneumonia in the nursing home.”

21. F. Blasi, M. Mantero, P. Santus, P. Tarsia. “Understanding the burden of pneumococcal disease in adults.”

22. M.L. Metersky, M.T. Dransfield, L.A. Jackson. “Determining the optimal pneumococcal vaccination strategy for adults: is there a role for the pneumococcal conjugate vaccine?”

23. B. Weinberger, B. Grubeck-Loebenstein. “Vaccines for the elderly.”