Journal Club Debunks Anti-Vaccine Myths

READ THE REST OF THIS ENTRY AT SCIENCE BASED MEDICINE

American Family Physician, the journal of the American Academy of Family Physicians, has a feature called AFP Journal Club, where physicians analyze a journal article that either involves a hot topic affecting family physicians or busts a commonly held medical myth. In the September 15, 2010 issue they discussed “Vaccines and autism: a tale of shifting hypotheses,” by Gerber and Offit, published in Clinical Infectious Diseasesin 2009.

The article presented convincing evidence to debunk 3 myths:

1. MMR causes autism.
2. Thimerosal (mercury) causes autism.
3. Simultaneous administration of multiple vaccines overwhelms and weakens the immune system, triggering autism in a susceptible host.

Gerber and Offit reviewed 13 large-scale studies that demonstrated no association between the MMR vaccine and autism. These included ecologic studies, retrospective observational studies and prospective observational studies.  The findings were consistent; the only outlier in all the studies of MMR was Dr. Andrew Wakefield’s small, discredited 1998 study, which was fully retracted by The Lancet in early 2010.

They reviewed 7 large-scale studies (again, ecologic, retrospective, and prospective) that consistently demonstrated no association between thimerosal and autism. They showed that the hypothesis was not biologically plausible, since the symptoms of mercury poisoning are distinct from those of autism and are not produced by the thimerosal in vaccines.

They showed that the overload hypothesis is not credible because

1. The immunologic load has dropped from 3000 components in the 7 vaccines used in 1980 to less than 200 in the 14 vaccines recommended today.
2. An infant’s immune system is capable of handling the thousands of antigens it is exposed to early in life.
3. Vaccinated children are not more susceptible to infections.
4. Autism is not an autoimmune disease.

READ THE REST OF THIS ENTRY AT SCIENCE BASED MEDICINE

 

 

New bivalent polio vaccine performs better than trivalent and just as well as monovalent vaccines

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A new study, published online at The Lancet shows that the bivalent polio vaccine, which is currently in use in India and Nigeria and offers protection against two of the polio virus strains, type 1 & 3, triggers a stronger immune response than the existing trivalent vaccine and similar immune response to the monovalent vaccines.

Immunogenicity of bivalent types 1 and 3 oral poliovirus vaccine: a randomised, double-blind, controlled trial

Dr Roland W Sutter MD a , Prof T Jacob John FRCP[E] b, Prof Hemant Jain MD c, Prof Sharad Agarkhedkar MD d, Prof Padmasini Venkat Ramanan MD e, Harish Verma MB f, Jagadish Deshpande PhD g, Ajit Pal Singh MB h, Meghana Sreevatsava MPH a, Pradeep Malankar MD a, Anthony Burton a, Arani Chatterjee MB h, Hamid Jafari MD f, R Bruce Aylward MD a

Study Summary – This was a double-blind, randomized,  controlled study which enrolled 830 babies in India, between August and December 2008. The researchers compared various oral polio vaccines’ efficacy in inducing an immune response, measured by the number of antibodies created after the doses were received (seroconversion). The total amount of antibodies was measured and compared after the first dose, and also after a second dose.

The babies were set up in 5 groups; it is not clear from the summary but it appears that each group would have received one of the following vaccines:

• monovalent type 1
• monovalent type 2
• monovalent type 3
• bivalent 1 & 3
• trivalent.

Although it is possible that some group may have been given a combination of monovalent vaccines; I am not sure. What does mono, bi, trivalent mean? It means this: the monovalent vaccines protect against one type only of the virus that causes polio. For example, monovalent type 1 protects against the Type 1 of the polio virus. Bivalent vaccines protect against two types at the same time, and trivalent vaccine protects against 3 types at the same time.

Immune response, or seroconversion, was measured after the first dose, and after the second dose of the vaccines. The responses were compared for the various vaccines.

Results – The results were as such:

Seroconversion after Dose 1

Type 1 Virus

• Monovalent  - 20%
• Bivalent – 20%
• Trivalent – 15%

Type 2 Virus

• Monovalent – 21%
• Bivalent – N/A
• Trivalent – 25%

Type 3 Virus

• Monovalent – 12%
• Bivalent – 7%
• Trivalent – 4%

Seroconversion after Dose 2 (cumulative)

Type 1 Virus

• Monovalent – 90%
• Bivalent – 86%
• Trivalent – 63%

Type 2 Virus

• Monovalent – 90%
• Bivalent – N/A
• Trivalent – 91%

Type 3 Virus

• Monovalent – 84%
• Bivalent – 74%
• Trivalent – 52%

The vaccines were well tolerated. 19 serious adverse events occurred, including one death; however, these events were not attributed to the trial interventions.

Conclusion – This study shows statistically significant differences between the bivalent and the trivalent vaccine, differences that become clearer after the second dose, at which point the bivalent vaccine outscored the trivalent one by more than 20% points for both polio viruses Type 1 and 2. There are no statistically significant differences between the bivalent and monovalent vaccines.

The conclusion following the results of this study is that, in this study the bivalent vaccine worked better than the trivalent vaccine in inducing an immune response, in infants. Further, the bivalent vaccine rates of seroconversion was just as good as the monovalent vaccines ones.

It is important to keep in mind though, that this study was only measuring the immune response, and does not draw any conclusions about the reduction of polio infections, hospitalizations or death rates. If that was the goal of the study, a proper placebo control would be absolutely necessary, but given that the purpose of the study was to compare efficacy of seroconversion rates as compared to the trivalent/monovalent vaccines, the use of a placebo is not necessary, since it is logical to assume that any placebo effects would similarly affect all groups of participants.

As such this study, in and off itself, does not lead to any conclusions about the bivalent vaccine’s efficacy in preventing polio infections, hospitalizations and deaths. We may extrapolate given it’s seroconversion rates, and what it is known about the monovalent/trivalent vaccines effects on polio infections/hospitalizations/death rates, but that would be just that, an extrapolation. The only question this study directly answers is: How does the bivalent polio vaccine compare to the monovalent and trivalent polio vaccines in inducing an immune response?

The authors concluded as such:

The findings show the superiority of bOPV compared with tOPV, and the non-inferiority of bOPV compared with mOPV1 and mOPV3.

Safety of influenza vaccine during pregnancy

Today we will look at the recent recommendation by the CDC, the American College of Obstetricians and Gynecologists,  that, all people over 6 months of age, including pregnant women receive the flu vaccine. Anti-vaccination groups have already come out,  insinuating that the safety of the flu vaccine given during a woman’s pregnancy has not been established. Is that true? Are there any studies that have looked at the safety of the influenza vaccine for pregnant women? The answer is yes, at the very least there is one that I was able to find, using simply Google.

Safety of influenza vaccination during pregnancy.

Munoz FM, Greisinger AJ, Wehmanen OA, Mouzoon ME, Hoyle JC, Smith FA, Glezen WP.

Study Summary – The objective of the study was to “evaluate the safety of influenza vaccine that is administered in the second or third trimester of gestation”. A retrospective electronic database search of 5 influenza seasons (July 1, 1998, to June 30, 2003) was performed at a large multispecialty clinic in Houston, Texas. Immunization rates were calculated, and outcomes of pregnancy were compared between healthy women who received influenza vaccine, and a control group of healthy unvaccinated women who were matched by age, month of delivery, and type of medical insurance.

Results - Among 7183 eligible mother-infant pairs, only 252 pregnant women (3.5%) received the influenza vaccine. The mean gestational age at the time of influenza vaccination was 26.1 weeks (range, 14-39 weeks). No serious adverse events occurred within 42 days of vaccination, and there was no difference between the groups in the outcomes of pregnancy (including cesarean delivery and premature delivery) and infant medical conditions from birth to 6 months of age.

Conclusion – This study provides good evidence that pregnant women who receive the flu vaccine during the last 2 trimesters of the pregnancy, and their babies at least up to 6 months of age, face no more risks or complications than pregnant women who do not receive the flu shot during the last 2 trimesters of their pregnancy, and their babies up to 6 months of age. It appears the claims of the anti-vaccination crowd are rejected, at least as far as this study is concerned.  The authors concluded as such:

Influenza vaccine that was administered in the second or third trimester of gestation was safe in this study population.

Maternal Flu Vaccination and Effect on Flu Infection in Young Infants

A new study, published online at the Archives of Pediatrics & Adolescent Medicine, looks at the effects of mom’s flu vaccine on young infants.

Maternal Influenza Vaccination and Effect on Influenza Virus Infection in Young Infants

Angelia A. Eick, PhD; Timothy M. Uyeki, MD, MPH, MPP; Alexander Klimov, PhD; Henrietta Hall, MS; Raymond Reid, MD; Mathuram Santosham, MD; Katherine L. O’Brien, MD, MPH

Arch Pediatr Adolesc Med. Published online October 4, 2010. doi:10.1001/archpediatrics.2010.192

Study Summary – The objective of this study was to assess the effect of seasonal influenza vaccination during pregnancy on laboratory-confirmed flu infections in infants up to 6 months of age. A total of 1160 mother-infant pairs were included in the study. The women gave birth during the regular flu season. Some of them received the flu vaccine, some didn’t. The assignment to either receive the flu vaccine or not was not random. The study authors looked at actual lab-confirmed influenza illnesses (ILI), and ILI hospitalization rates of the infants as the main outcomes. They compared ILI confirmed rates, and ILI hospitalization rates between the infants born to vaccinated mother and infants born to unvaccinated mothers.

Results – Infants born to vaccinated mothers were less likely than infants born to unvaccinated mothers to contract ILI. Specifically:

• 41% reduction in the risk of laboratory-confirmed influenza virus infection (relative risk, 0.59; 95% confidence interval, 0.37-0.93)
• 39% reduction in the risk of ILI hospitalization (relative risk, 0.61; 95% confidence interval, 0.45-0.84)
• Significantly higher hemagglutinin inhibition antibody levels at birth and at 2 to 3 months of age

Conclusion - Methodologically, the main design issue is that test subjects were not assigned randomly to either the vaccine or no-vaccine. Furthermore, it appears from the abstract at least, that the mothers in the no-vaccine group did nor receive a placebo shot. The implication is that they simply did not receive a shot and were aware of it, which would affect the blinding as well.

When taken together these two facts should lower our reliance on the results, although not negate it entirely. The differences of 41% and 39% are too big to be due simply to bias introduced by these design issues. So the conclusion should be that given the large sample size and the large differences between the two groups, this study is highly indicative that babies born to vaccinated mothers do receive a tangible benefit from the vaccine, but the actual reduction in infection and hospitalization rates may be a little less than the numbers reported in this study. These conclusions should be compared to other studies, hopefully studies that had better blinding and randomization.

The author’s own conclusion is as such;

Maternal influenza vaccination was significantly associated with reduced risk of influenza virus infection and hospitalization for an ILI up to 6 months of age and increased influenza antibody titers in infants through 2 to 3 months of age.

3-dose 7-Valent pneumococcal vaccine use associated with increased nasopharyngeal acquisition of pneumococcal Serotype 19A Strain

A recent study published in the Journal of the American Medical Association (JAMA) has found an association between the 7-valent pneumococcal vaccine (PCV-7) and an increase in nasopharyngeal (in the nose and throat) acquisition of pneumococcal serotype 19A strain, which is not one of the 7 strains the PCV-7 protects from. According to the authors of the study, a possible association had been observed between the use of PCV-7 vaccine and a rapid increase in serotype 19A strain acquisition, but studies had never been done to confirm this association, and the current study is the first one to address that concern. Let us look at it:

Pneumococcal Conjugate Vaccination and Nasopharyngeal Acquisition of Pneumococcal Serotype 19A Strains

Elske J. M. van Gils, MD; Reinier H. Veenhoven, MD, PhD; Eelko Hak, PhD; Gerwin D. Rodenburg, MD; Wendy C. M. Keijzers; Debby Bogaert, MD, PhD; Krzysztof Trzcinski, DVM, PhD; Jacob P. Bruin; Loek van Alphen, PhD; Arie van der Ende, PhD; Elisabeth A. M. Sanders, MD, PhD

JAMA. 2010;304(10):1099-1106. doi:10.1001/jama.2010.1290

Study Summary – The study was conducted in the Netherlands. 948  healthy infants, from 6 weeks up to 24 months of age, were enrolled, and followed between July 7, 2005, and February 14, 2008. Infants were randomly assigned to receive 2 doses of PCV-7 at 2 and 4 months; 2 + 1 doses of PCV-7 at 2, 4, and 11 months; or no dosage (unvaccinated control group). Nasopharyngeal swabs were obtained at the age of 6 weeks and at 6, 12, 18, and 24 months to test for the presence of the 19A strain of the pneumococcal bacteria. Rates of bacterial presence were compared between the different groups.

Results - 54 nasopharyngeal serotype 19A carriage isolates from 318 in the 2-dose group, 66 isolates from 327 in the 2 + 1-dose group, and 33 isolates from 303 in the unvaccinated were collected from 6 weeks through 24 months. The cumulative proportion who tested positive for new nasopharyngeal serotype 19A acquisition from 6 through 24 months of age was significantly higher in those having received the 2 + 1-dose PCV-7 schedule (16.2%; 95% confidence interval [CI], 12.6%-20.6%) vs those who were unvaccinated (9.2%; 95% CI, 6.5%-13.0%; relative risk [RR], 1.75; 95% CI, 1.14-2.70) but not after a 2-dose schedule (13.2%; 95% CI, 9.9%-17.4%; RR, 1.43; 95% CI, 0.91-2.25).

Conclusion - This study is methodologically sound. The sample size was fairly large, subjects were randomly assigned, and there was a proper control group. If the results of this study hold, and can be replicated, it would strongly suggest that a 3-dose of the PCV-7 pneumococcal vaccine might lead to higher rates of acquisition of the 19A strain in infants between 6 weeks and 24 months of age. It is very interesting that there were no statistically significant differences between the non-vaccinated children and the ones that had not received the 3rd dose yet. From the information that can be gleamed by the abstract of the study, the authors don’t seem to speculate on why it appears that the 3rd dose makes the difference. They conclude simply as such:

A 2 + 1-dose PCV-7 schedule was associated with an increase in serotype 19A nasopharyngeal acquisition compared with unvaccinated controls.

How should we interpret this study? By the author’s own admission, this is the first study to look at the association between PCV-7 and increased serotype 19A acquisition rates. As such, it is imperative that its results be replicated, to rule out mistakes, or other things that could have affected the results. On the other hand, the study looks to have been conducted well, and appears to have been designed properly. It provides intriguing evidence that 3 doses of the PCV-7 vaccine might be causally related to an increase in nasopharyngeal acquisition of pneumococcal serotype 19A Strain. More studies are needed to verify these results.

Until then, the best course of action is to speak to your pediatrician, and talk to her about using the 13, or the 23, valent version of the pneumococcal vaccine which also covers serotype 19A strains of the pneumococcal bacteria. You should not unilaterally decide to skip the pneumococcal vaccination completely based solely on this one study.

Vaccines don’t raise arthritis risk in adults

READ THE FULL ARTICLE AT DOTmed.COM

Common vaccinations don’t raise risk of rheumatoid arthritis, easing fears that they’re linked to the inflammatory disease, according to a new study.

Case reports have suggested vaccines, possibly because of their immune-activating adjuvants, could trigger rheumatoid arthritis, a painful autoimmune disease caused by the body’s natural defenses attacking and inflaming joints.

But a study published online Tuesday in the Annals of the Rheumatic Diseases found no link between common vaccinations for flu, hepatitis, diphtheria and other illnesses and an increased risk for rheumatoid arthritis. The study also found no increased risk for patients getting vaccinations who had a genetic susceptibility to the disease, or who were smokers. Smoking has long been thought to be a major risk factor for the disease.

Receiving multiple vaccines also didn’t up the chances of getting afflicted by the joint disease.

“Our results indicate that immunological provocation of adults with common vaccines in their present form is not a major risk factor for RA,” write the authors, led by Camilla Bengtsson, a researcher at the Karolinska Institute in Stockholm, Sweden. “In addition, our results indicate that active immunization does not increase the risk of RA in individuals with established risk factors.”

READ THE FULL ARTICLE AT DOTmed.COM

Reduction in Gastroenteritis With the Use of Pentavalent Rotavirus Vaccine in a Primary Practice

I have previously looked at studies that looked at acute gastroenteritis (AGE) rates of hospitalizations before and after the introduction of the pentavalent rotavirus vaccine (RV5). Those studies noted a significant reduction in AGE hospitalization rates following the introduction of the RV5 in 2006. In this entry, I will summarize yet another study along the same lines.

AGE, 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 among 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.

The study we will look at today, was published in the journal Pediatrics and the abstract can be accessed by clicking the link below.

Reduction in Gastroenteritis With the Use of Pentavalent Rotavirus Vaccine in a Primary Practice

Rodolfo E. Bégué, MDa, Keith Perrin, MDb

Study Summary – The authors followed up children under 5 years of age, who presented with AGE in a large pediatrics practice in New Orleans, between 2004 and 2009. Primary care physician office visits, emergency department visits, and hospital admissions were identified by review of records. RV testing was performed only on those who were seen at the hospital. Overall, about 16,000 children were included in this study.

Results - For 2006–2007, 2007–2008, and 2008–2009, 11.1%, 40.3%, and 45.6% of age-eligible children, respectively, received 1 dose of RV5.  As compared with 2004–2005 (before RV5), in 2007–2009, there was a significant decrease in all-cause AGE office visits (23%) and hospitalizations (50%). RV-positive cases (emergency department visits or hospitalizations) decreased by 67%. The decrease in RV-positive cases was more evident among children who were younger than 2 years (81%), with a strong trend among those who were aged 2 to <5 years (41%).

Conclusion - This study adds more evidence that the introduction of the pentavalent rotavirus vaccine led to a significant decrease in all-cause AGE hospitalizations, and especially rotavirus-caused AGE. Taken together with the previous 3 studies we’ve reviewed, the evidence seems very solid and is strongly suggestive of a correlation between the introduction of RV5 in 2006, and significant decreases in AGE hospitalizations. The authors of the above study concluded as such:

Increased use of RV5 in a pediatric practice was associated with fewer AGE office visits and hospitalizations. The reduction was specific for RV-positive AGE and seen among children who were targeted for immunization as well as older groups, suggesting a herd-immunity effect.

Study links combination MMRV vaccine with double the risk for febrile seizures

The MMRV vaccine is a combination vaccine, which combines the MMR vaccine and the Varicella vaccine in a single dose. The MMR vaccine itself is a combination vaccine, providing protection from Measles, Mumps and Rubella. A recent study, published in the journal Pediatrics, shows that the risk for febrile seizures, in the 7-10 day period following receipt of the MMRV vaccine, is twice as big as compared to receiving separate MMR & Varicella vaccines in the same day, for children 12-23 months of age.

Measles-Mumps-Rubella-Varicella Combination Vaccine and the Risk of Febrile Seizures

Nicola P. Klein, Bruce Fireman, W. Katherine Yih, Edwin Lewis, Martin Kulldorff, Paula Ray, Roger Baxter, Simon Hambidge, James Nordin, Allison Naleway, Edward A. Belongia, Tracy Lieu, James Baggs, and Eric Weintraub for the Vaccine Safety Datalink 2010;126;e1-e8; originally published online Jun 29, 2010; Pediatrics DOI: 10.1542/peds.2010-0665

Study Summary – The researchers used 2000–2008 Vaccine Safety Datalink data to compare seizures and fever visits, restricted to emergency room or hospital visits,  among children aged 12 to 23 months, during the 42 days after receipt of the MMRV vaccine, or the separate MMR +
varicella vaccines. The study population included 83, 107 children vaccinated with MMRV between January 2006 and October 2008 and 376, 354 vaccinated with MMR
varicella between January 2000 and October 2008.  The secondary comparison groups consisted of 145, 302 children who received MMR vaccine alone and 107, 744 who received varicella vaccine alone from 2000 to 2008. The authors monitored weekly seizure visits and compared the rates between the vaccines.

Results - After vaccination with all measles-containing vaccines, seizure incidence peaked during days 7 to 10; the most prominent peak was recorded after MMRV vaccination. During days 7 to 10, unadjusted rates for seizures were 84.6 seizures per 1000 person-years after MMRV vaccination, 42.2 seizures per 1000 person-years after MMR
+ varicella vaccination, and 26.4 seizures per 1000 person-years after MMR vaccination alone. Unadjusted rates during days 7 to 10 were nearly 8 times higher for MMRV and 4 and 3.5 times higher for MMR
varicella and MMR vaccination alone, as compared to Varicella vaccine alone.

Conclusion – The study looked at over 459 000 children, 12-to-23 months of age, who were vaccinated with either the MMRV vaccine, or separate MMR & Varicella vaccines, and found the MMRV to be associated with increased fever and seizures 7-10 days following vaccination. When compared to separate MMR + Varicella vaccine received at the same time, the combination MMRV vaccine was associated with a two-fold increase in risk of having a febrile seizure in the 7-10 days following vaccination. The authors estimated this meant 1 additional case of febrile seizure for every 2,300 doses of MMRV vaccine given, as compared to separate MMR & Varicella vaccines received at the same time. There was no difference in seizure risk outside of the 7-10 day window. The study shows that both MMRV, and MMR+Varicella vaccines are associated with increased seizure risk in the 7-10 day window, as compared to Varicella vaccine alone, with the risk from MMRV being twice as high as the separate MMR+Varicella vaccinations. Here is what the authors of the study had to say:

Among 12- to 23-month-olds receiving their first dose of measles-containing vaccine, the risk of fever and seizure are elevated 7 to 10 days after vaccination. The use of MMRV vaccine instead of separate MMR
varicella vaccines approximately doubles the risk for fever and febrile seizures, resulting in 1 additional febrile seizure for every 2300 doses of MMRV vaccine administered instead of separate MMR and varicella vaccines.

Bottom Line:  Talk to your pediatrician about this; it appears the best route is to take the separate MMR+Varicella vaccines as opposed to the single MMRV shot. Febrile seizures are fairly common, with 1 in 25 children experiencing at least one seizure. While witnessing a child going through one is scary, they are generally harmless. According to the National Institute of Neurological Disorders and Stroke:

Although they can be frightening to parents, the vast majority of febrile seizures are harmless. During a seizure, there is a small chance that the child may be injured by falling or may choke from food or saliva in the mouth. Using proper first aid for seizures can help avoid these hazards (see section entitled “What should be done for a child having a febrile seizure?”).

There is no evidence that febrile seizures cause brain damage. Large studies have found that children with febrile seizures have normal school achievement and perform as well on intellectual tests as their siblings who don’t have seizures. Even in the rare instances of very prolonged seizures (more than 1 hour), most children recover completely.

Between 95 and 98 percent of children who have experienced febrile seizures do not go on to develop epilepsy. However, although the absolute risk remains very small, certain children who have febrile seizures face an increased risk of developing epilepsy. These children include those who have febrile seizures that are lengthy, that affect only part of the body, or that recur within 24 hours, and children with cerebral palsy, delayed development, or other neurological abnormalities. Among children who don’t have any of these risk factors, only one in 100 develops epilepsy after a febrile seizure.

Vaccine Safety & Efficacy-Flu vaccine

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.

Safety and immunogenicity of trivalent inactivated influenza vaccine in infants: a randomized double-blind placebo-controlled study.

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.

Rotavirus vaccine shown to be effective in preventing gastroenteritis in 2 new studies in Asian and African populations

Two new studies, published online in The Lancet (the full text can be accessed here and here; free registration to The Lancet required), have produced similar results to the results of a similar US study on which I reported here at Vaccine Central which showed the RotaTeq pentavalent rotavirus vaccine to be 45% in reducing all cause gastroenteritis hospitalization rates, an excellent track record given that the rotavirus is credited with causing up to 50% of all cause gastroenteritis hospitalizations in children. At that time, I concluded that although the study showed a strong correlation between the introduction of the vaccine and the reduction in AGE hospitalization rates, given that we only had 2 data points, we couldn’t make a direct causation link between the two events, and that further evidence was needed in order to reach that conclusion.

That further evidence has been provided by the above-mentioned 2 studies. I will summarize each study separately.

ASIAN STUDY

Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial

K Zaman, Dang Duc Anh, John C Victor, Sunheang Shin, Md Yunus, Michael J Dallas, Goutam Podder, Vu Dinh Thiem, Le Thi Phuong Mai,Stephen P Luby, Le Huu Tho, Michele L Coia, Kristen Lewis, Stephen B Rivers, David A Sack, Florian Schödel, A Duncan Steele, Kathleen M Neuzil,Max Ciarlet

Study Summary-This was a multicentre, double-blind, placebo-controlled trial, undertaken in rural Matlab, Bangladesh (2 year observation period), and urban and periurban Nha Trang, Vietnam (One and a half years observation period). Infants aged 4–12 weeks without symptoms of gastrointestinal disorders were randomly assigned (1:1) to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age. Infants who received vaccine or placebo were visited once a month to remind parents to bring their child to a clinic or hospital if their child developed symptoms of gastroenteritis. Any adverse reactions occurring within 14 days of receipt of each dose (both vaccine and placebo) were recorded.

To assess immune responses to vaccination, a small amount of venous blood was obtained immediately before the first dose of study vaccine or placebo was given and about 14 days after the third dose was given in a subset of around 300 participants (around 150 per site).

The primary outcome was severe rotavirus gastroenteritis, irrespective of serotype, occurring 14 days or more after the third dose of vaccine or placebo until end of study. Secondary outcomes were efficacy of vaccination against rotavirus gastroenteritis of any severity, proportion of participants with a serious adverse event within 14 days of any dose, and the proportion of participants with seroresponse for antirotavirus IgA.

Results – Overall, the vaccine had a success rate of 48.3% in preventing severe rotavirus gastroenteritis (RVGE), 42.5 % reduction in any severity RVGE, and 27% in severe GE of any cause. Seroresponse, rotavirus antibodies present in the blood stream, was significantly  higher in the vaccinated groups (87.8%) than the placebo group (18.2%).  Serious side effects within 14 days of any dose were virtually the same for both the vaccine and the placebo group (Table 5).

Conclusion - The study is methodologically sound. It is randomized, double-blind and placebo-controlled. The results strongly suggest that the pentavalent rotavirus vaccine reduces both RVGE and all cause GE rates, by about 48% and 27% respectively, while being safe and inducing a strong immune system response in the participants. Side effects for the vaccinated children were comparable to those of the children in the control group.

Conflicts of Interest – The study was designed and run by Merck, one of the vaccine makers, with input from World Health Organization staff and site investigators. Here is the complete “Role of funding source” section from the study:

The study was designed by Merck investigators, with substantial input from PATH staff and site investigators. Merck had direct oversight or participation in every stage of the study. Merck also participated in pharmacovigilance, organised and led the data and safety monitoring board meetings, and did the data analysis. Staff from PATH independently monitored study execution at sites and participated in pharmacovigilence, data analysis, and data and safety monitoring board meetings. All authors had full access to the data, and the corresponding author had final responsibility for the decision to submit for publication.

AFRICAN STUDY

Effi cacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind,
placebo-controlled trial
George E Armah, Samba O Sow, Robert F Breiman, Michael J Dallas, Milagritos D Tapia, Daniel R Feikin, Fred N Binka, A Duncan Steele, Kayla F Laserson, Nana A Ansah, Myron M Levine, Kristen Lewis, Michele L Coia, Margaret Attah-Poku, Joel Ojwando, Stephen B Rivers, John C Victor, Geoff rey Nyambane, Abraham Hodgson, Florian Schödel, Max Ciarlet, Kathleen M Neuzil

Study Summary – The design of this study is identical to that of the Asian study. The only difference is the number of children; the African study enrolled about twice as many subjects. 5468 infants, in Ghana, Kenya and Mali, were randomly assigned to receive pentavalent rotavirus vaccine (n=2733) or placebo (n=2735) with an observation period of 23 months. Immune responses to vaccination were assessed in a subset of around 450 participants (around 150 per site). Primary and secondary outcomes were identical to the Asian study.

Results - Overall, the vaccine had a success rate of 39.3% in preventing severe rotavirus gastroenteritis (RVGE), 30.5 % reduction in any severity RVGE, and 10.6% in severe GE of any cause. Seroresponse, rotavirus antibodies present in the blood stream, was significantly  higher in the vaccinated groups (78.3%) than the placebo group (20.1%).  Serious side effects within 14 days of any dose were virtually the same for both the vaccine and the placebo group (Table 5).

Conclusion - The study is methodologically sound. It is randomized, double-blind and placebo-controlled. The results strongly suggest that the pentavalent rotavirus vaccine reduces both RVGE and all cause GE rates, by about 30.5% and 10.6% respectively, while being safe and inducing a strong immune system response in the participants. Side effects for the vaccinated children were comparable to those of the children in the control group.

Conflicts of Interest – The study was designed and run by Merck, one of the vaccine makers, with input from World Health Organization staff and site investigators. Here is the complete “Role of funding source” section from the study:

The study was designed by scientists from Merck, with substantial input from PATH staff and site investigators. Merck had direct oversight or participation in every stage
of the study. Merck also participated in pharmacovigilance, organised and led the data and safety monitoring board meetings, and did the data analysis. Staff from PATH
independently monitored study execution at sites and participated in pharmaco vigilance, data analysis, and data and safety monitoring board meetings. All authors had full access to the data, and the corresponding author had final responsibility for the decision to submit for publication.

Where do these 3 studies leave us?

It is important to note, that while all 3 studies (US, Asia and Africa) point to the same direction, and all three show that the pentavalent rotavirus vaccine does have a substantial effect in reducing all cause gastroenteritis cases, the actual effect size of the vaccine seems to vary considerably from region to region. The US study reported a 45% decrease in all cause AGE hospitalization rates; the Asian study reported a 27% decrease while the African study reported a 10.6% decrease. The authors have picked up on this as  well and have included this issue in their discussion. For example, this is what they say in the African study:

Although the efficacy noted in this trial and the accompanying study in Asia were significant, both estimates of efficacy were lower than that reported with pentavalent rotavirus vaccine in developed countries or in developing countries in Latin America. Direct comparisons of results from previous studies of pentavalent rotavirus vaccine are limited by differences in study design, collection procedures, and clinical scoring systems. However, the comparatively low efficacy noted in this study is consistent with the low efficacy with another rotavirus vaccine reported in Africa compared with more developed countries, and with the low efficacy reported in low-income populations with other orally administered vaccines. The immunogenicity of pentavalent rotavirus vaccine in our study population was substantially lower than were results obtained in more developed countries.

So why this variation? It’s hard to say, it does not seem clear to me from these studies at least, why there would be such variation. As far as the US study is concerned, part of the answer may have to do with the fact that it was a retrospective study, comparing rates before vaccination with rates after vaccination, thus lacking a proper control group which the Asian and African studies had. On the other hand geography seems to have an important effect, as even within the Asian group there were some considerable differences between the two countries.

Nevertheless, while these issues may need more time to be sorted out, the take-home message is a very encouraging one: the pentavalent rotavirus vaccine seems to have a considerable positive effect in reducing all cause gastroenteritis rates in infants, while being safe. And given that there are an estimated 527,000 rotavirus deaths worldwide per year, even if the true effect turns out to be the lowest value of the three, the 10.6%, we are still talking about roughly 56,000 lives saved per year, with basically next to zero side effects from the vaccine.