Today we will look at a study about the efficacy and safety of the flu vaccine in infants. The study was published in The Pediatric Infectious Disease Journal in February 2010.
Englund JA, Walter E, Black S, Blatter M, Nyberg J, Ruben FL, Decker MD; GRC28 Study Team.
Study Summary- This was a double-blind, randomized, placebo-controlled trial, conducted in 1375 healthy US infants 6 to 12 weeks of age. Subjects received 2 doses of trivalent inactivated influenza vaccine (TIV, Fluzone, Sanofi Pasteur; N = 915) or placebo (N = 460) 1 month apart in combination with indicated concomitant vaccines. Solicited adverse events were collected for 7 days following vaccination, and unsolicited adverse events for 28 days. Antibodies to all 3 vaccine strains were measured following the second TIV/placebo dose.
Results – No significant differences were seen between TIV and placebo groups for any safety outcome. Fever > or =38 degrees C within 3 days of vaccination was seen in 11.2% versus 11.7% of TIV versus placebo recipients. Serious adverse events within 28 days were reported in 1.9% of TIV and 1.5% of placebo recipients. Antibody responses to childhood vaccines were similar in both groups. Increased influenza-specific antibody responses in TIV recipients compared with placebo recipients were seen against all 3 strains in TIV recipients, with better responses to influenza A strains noted. Reciprocal geometrical mean titer to H1N1, H3N2, and B were 33, 95, and 11 in TIV recipients versus 7, 9, and 5 for placebo recipients.
Conclusion – This study fulfills all the basic requirements for a well designed scientific study. The sample was large (1,375 participants); it was double-blind, randomized and placebo controlled. This study showed that the trivalent, inactivated flu vaccine was just as safe as the placebo and highly more efficient than placebo in inducing antibody response to all three strains of the virus. The authors concluded as such:
TIV administered to young infants beginning at 6 to 12 weeks of age is safe and immunogenic.
“Pneumonia vaccine ineffective against repeat infections: study” screams the headline. The article goes on to clarify that a study just published seems to suggest that the pneumococcal vaccines in use in Canada do not seem to perform any better than no vaccine. How is that possible? Well, so far as I can tell, it isn’t, and this seems to be another case of dubious reporting by the journalists, and careless conclusions by paper authors.
I could not get my hands on a copy of the full published study the article refers to, although I will probably be able to in the near future. In the mean time, all I can go on is the abstract which can be found at PubMed or at Chicago Journals. Let us examine exactly what this study seems to suggest, based on the publicly available abstract.
Background.There is debate surrounding the effectiveness of the 23‐valent pneumococcal polysaccharide vaccine (PPV). We determined whether PPV was associated with reduced mortality or additional hospitalization for vaccine‐preventable infections in patients previously hospitalized for community‐acquired pneumonia (CAP).
Ok, so first thing to keep in mind: they only studied people who got pneumonia. This is not a study comparing vaccinated vs. unvaccinated, and seeing if there is any protection offered by the vaccine in the form of reduced infection rates. This is a study consisted of only people who got sick, breaking those down into two groups and seeing how each group fared.
Now, it is an accepted fact that no vaccine is 100% effective, meaning that no vaccine will prevent the disease on all people who receive it. For one reason or another, some people get no benefit from any given vaccine. Those people will get sick from the disease, regardless of their vaccination status. By definition, if you are gathering together people who are sick in the hospital, you are already limiting yourself to only that subset of the vaccinated population for whom the vaccine has already failed. So from that point alone, this is like saying “Well let me find all the people for whom the vaccine failed & let me measure how effective the vaccine was for them“. Just to make a comparison, this sounds kind of like saying “let me find out which team lost, and see how likely they are to have won!“.
Results.A total of 2950 patients were followed up for a median of 3.8 years. The mean patient age was 68 years; 52% were male. One‐third (n=956) received PPV: 667 (70%) before and 289 (30%) during hospitalization. After discharge, 1404 patients (48%) died, 504 (17%) were admitted with vaccine‐preventable infections, and 1626 (55%) reached the composite outcome of death or infection. PPV was not associated with reduced risk of the composite outcome (589 [62%] vs 1037 [52%] for those unvaccinated; adjusted hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.79–1.04). Results were not altered in sensitivity analyses using propensity scores (adjusted HR, 0.91; 95% CI, 0.79–1.04), restricting the sample to patients 65 years or older (adjusted HR, 0.90; 95% CI, 0.77–1.04), or considering only those who received PPV at discharge (adjusted HR, 0.84; 95% CI, 0.71–1.00).
Second point to keep in mind; the mean patient age was 68 years. The study is itself limited to only “adults at high risk for pneumonia”. So at best, the results of this study might hold for adults, average 68 years old, for whom the vaccine has already failed to offer immune protection. That is quite a small subset of all people who get the vaccine. The question to ask ourselves is: how reliable are such results and how can they be applied to the total vaccinated population?
Conclusions.One‐half of patients discharged from the hospital after pneumonia die or are subsequently hospitalized with a vaccine‐preventable infection within 5 years. PPV was not associated with a reduced risk of death or hospitalization. Better pneumococcal vaccination strategies are urgently needed.
And this is the careless conclusions that I was referring to: “Better pneumococcal vaccination strategies are urgently needed.” Better than what? That is the confusing part. If you choose to only look at the people for whom the vaccine has already failed, what really do you expect the results to be? If the person got sick, the vaccine failed to protect them. If the vaccine failed, wouldn’t we expect both failed-vaccinated and unvaccinated groups to show the same pattern? What insight can one gain by looking at the failed vaccine group? Confirmation that a vaccine that failed to prevent the disease in the person, also fails to reduce mortality rates from the disease? So this study possibly tells us that in people over 68, when the pneumococcal vaccine fails, it fails completely. Hmm, ok, isn’t that kind of to be expected anyway?
How can these results support the conclusion that better pneumococcal vaccination strategies are urgently needed though? The study did not examine pneumococcal vaccine efficacy, like this one properly did, by comparing vaccinated vs. placebo shots and checking out infection and morbidity rates. The only question this study aimed to answer is this: When the vaccine fails to build immunity, does it also fail to protect from death? And the answer, unsurprisingly, is coming back to be yes.
Maybe some vaccines reduce death rates from the disease even if they fail to build immunity against the disease. I guess that is plausible; I don’t know enough to say. However, it appears to me that, the way this study was designed, the way the groups were chosen, leaves a lot to be desired and seems to be set up so as to provide only one possible answer. This study seems better equipped to figure out the mortality rate from pneumococcal than the efficacy of the pneumococcal vaccine. The authors should be more careful with their conclusions and keep in mind the limits of their design; they should be the first ones to acknowledge that their study cannot be generalized to the whole vaccinated population. Yet, somehow they fail to do that and instead make unwarranted conclusions about improving vaccination strategies. That coupled with journalists looking for sensational headlines unfortunately has the effect of sending a message to the public that is not supported by the science. And that is sad; sad and dangerous.
REMINDER: These comments should be held as temporary until I get my hands on the full PDF. That will either verify that my interpretation of the abstract is correct, or I will have to come back and modify my interpretation.
A new analysis, published online by The Journal of Infectious Diseases, takes a look at acute gastroenteritis hospitalization (AGE) rates among US children under 5 years old, before and after the introduction of the first Rotavirus vaccine, RotaTeq (RV5) in early 2006. The objective of this analysis was to see if there was any change in gastroenteritis hospitalization rates after the vaccine was licensed for use among infants in the United States. The study I am referring to is this one:
Aaron T. Curns, Claudia A. Steiner, Marguerite Barrett, Katherine Hunter, Emily Wilson, and Umesh D. Parashar
The Journal of Infectious Diseases 2010;201:1617–1624 © 2010 by the Infectious Diseases Society of America. All rights reserved.
Why did they look at gastroenteritis hospitalization rates? Because that disease, commonly referred to as the “stomach flu“, is a viral infection, and rotavirus is the leading cause of severe gastroenteritis in children, credited with causing about 50% of acute gastroenteritis hospitalizations during January-June amoung U.S. children. Logically, if rotavirus causes it, and if an effective vaccine is introduced, we ought to observe statistically significant decreases in gastroenteritis hospitalization rates, and this is what this analysis was set up to do.
Study Summary -The authors gathered approximately 100% complete AGE hospitalization rates for children under 5 years of age, from 18 states, accounting for 49% of the U.S. under 5 children population. Median AGE hospitalization rates from the pre-vaccine years of 2000-2006 were compared with median AGE hospitalization rates from 2007, the first year after the vaccine, and 2008.
Results – Overall AGE hospitalization rates went down by 16% in 2007 and decreased by 45% in 2008. By age group, the reductions line up like this:
- 0-2 months – 28%
- 3-5 months – 42%
- 6-23 months – 50%
- 24-59 months – 45%
Prior to RV5 introduction, children in the 6-11 month age group had the highest hospitalization rates; after vaccine introduction children in the 0-2 month age group had the highest hospitalization rates, and showed the lowest decreases. Given that the first dose of the vaccine is given at 2 months of age, this result is to be expected.
All states experienced reduced rates of hospitalization with the exception of two: Arizona and Nevada which experienced increases of 17.1% and 12.9% respectively, prompting the study authors to note that :
It is noteworthy that 2 participating states, Arizona and Nevada, had 2008 rotavirus seasons that were similar to those in prior seasons. As data become available, it will be of interest to evaluate whether these 2 states had different patterns of RV5 coverage that could explain their distinct 2008 rotavirus seasons.
How should we interpret this analysis? Well, as alwasy the rule of thumb is that one study never proves anything. However, this study does provide strong evidence for a correlation between the RV5 vaccine and lower AGE hospitalization rates. We have to be careful though to remember that correlation does not necessarily imply causation. Given that the post-vaccine data is only for two years, the conclusion that the introduction of the rotavirus vaccine lowered AGE hospitalization rates seems unwarranted at this point. It will be interesting to see if these results hold up 2, 5, 10 years down the road.
Nevertheless, the fact that rotavirus is responsible for 50% of AGE hospitalizations, and the fact that the reductions were more pronounced in the age groups that received vaccines, as compared to the 0-2 month olds who do not, suggests a correlation to some degree. Furthermore, while there is year-to-year variability in AGE hospitalization rates, the 2008 reduction “well exceeded the range of this variability” further suggesting an effect other than regular variability. Lastly, the “consistency of the decrease in acute gastroenteritis hospitalization rates across most states and specifically during the rotavirus season strongly support that these changes resulted from the RV5 vaccination, but the lack of timely national data on RV5 coverage precluded correlation of the decreases with vaccine uptake.” (emphasis added)
Conclusion – This analysis provides good evidence for an association between the introduction of the RV5 vaccine and a considerable reduction in AGE hospitalization rates, especially for 2008. It also provides strong evidence that there may be a correlation between the two, however the lack of nationals RV5 coverage data, and the fact that the post vaccine years provide only 2 data points, preclude us from concluding that the decreases are due to the vaccine. Only further confirmatory studies down the road can provide that additional support that would be needed to conclusively say that the rotavirus vaccine has had a direct effect in reducing AGE hospitalization rates. Until then, we must stick with the strong suggestion that it does.
Are vaccines effective? That is another question that worried parents often ask. Do we know for sure that these vaccines do what they are supposed to do? Well, as I’ve said before, that question is very broad, so we will try to break it down into manageable bits. This entry will look and see if we can find any evidence for the efficacy of the pneumococcal vaccine in preventing pneumonia and pneumonia deaths. As usual, PubMed makes for an excellent start. A quick search there brings up this interesting study.
Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and placebo controlled trial. Maruyama T, Taguchi O, Niederman MS, Morser J, Kobayashi H, Kobayashi T, D’Alessandro-Gabazza C, Nakayama S, Nishikubo K, Noguchi T, Takei Y, Gabazza EC. Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu City, Mie Prefecture, Japan. BMJ. 2010 Mar 8;340:c1004. doi: 10.1136/bmj.c1004.
Study Summary – The study was set up to examine the efficacy of the pneumococcal vaccine in preventing pneumonia and/or reducing pneumonia-related deaths. There were a total of 1006 participants from nursing homes in Japan. They were randomly split into two virtually equal groups (in size); one group received the vaccine, the other a placebo. The study was double-blind, meaning that non only did the participants not know if they were on the vaccine or placebo, but those administering the doses did not know either. The results showed a 39.32% decrease in all-cause pneumonia infections between the placebo and the vaccinated group (form 20.6% in the placebo group to 12.5% in the vaccine group). As far as pneumococcal pneumonia rates were concerned, it also showed a decrease, this time of 61.64%. Furthermore, no deaths occurred amongst those in the vaccinated group that developed pneumococcal pneumonia, whereas the placebo group had a death rate of 35.1%. However, death rate from ALL CAUSE pneumonia did not differ between the two groups. The study’s conclusion was as such:
CONCLUSION: The 23-valent pneumococcal polysaccharide vaccine prevented pneumococcal pneumonia and reduced mortality from pneumococcal pneumonia in nursing home residents
So how should we interpret this study? I interpret it like this: the pneumococcal vaccine was significantly effective (as compared to placebo) in preventing both infections and deaths by pneumococcal pneumonia. The vaccine appears to be highly effective for the age group the study investigated. It also significantly decreases all-cause pneumonia infections, but appears to have no effect in death rates for all-cause pneumonia.