VACCINOLOGY UPDATE

Acellular pertussis vaccine at birth lowered toxoid IgG antibodies

Children who received a monovalent acellular pertussis vaccine at birth had lower pertussis toxoid immunoglobulin G antibodies after the booster dose compared with children who received their first dose at age 8 weeks, according to recent study findings published in The Pediatric Infectious Disease Journal.

Nicholas Wood of the National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases in Australia, and colleagues evaluated 76 neonates between 2007 and 2010 to determine antibody and cell-mediated immunity to pertussis 4 years after vaccination. Participants were randomly assigned into three groups: acellular pertussis vaccine and hepatitis B vaccine within 4 days of birth and an additional acellular pertussis vaccine at age 4 weeks (group 1); two acellular pertussis and hepatitis B vaccines at birth (group 2); and only hepatitis B at birth (group 3).

At age 2 years or before and after the 4-year diphtheria-tetanus toxoids-acellular pertussis-polio immunization (DTaP-IPV; Infanrix IPV, GSK Biologicals), pertussis toxoid, filamentous hemagglutinin and pertactin antibody levels were similar among all three groups. Group 1 had higher anti-pertussis antibody levels at age 8 months, but levels were similar among all three groups at age 2 years.

All participants had detectable pertussis antibody levels to pertussis toxoid and pertactin at age 8 months compared with 15% to 18% at age 2 years and 9% to 14% right before the DTaP-IPV booster at age 4 years. However, filamentous hemagglutinin IgG levels were stable from age 2 to 4 years.

Groups 1 and 2 had higher T-helper cell type 2 (Th2) levels compared with group 3.

“In this study, pertussis antibody levels waned significantly by 2 to 4 years old, with <20% having detectable antibodies to both [pertussis toxoid] and [pertactin], thought to equate with protection, and this has implication for the timing of the booster dose of DTaP vaccines, particularly in Australia where a booster dose is no longer given in the second year of life,” the researchers wrote. “We found a non-significant trend to lower [pertussis toxoid] IgG antibodies post the 4 year booster compared with receipt of first dose of [acellular pertussis]-containing vaccine at 8 weeks of age. We also found higher levels of [Th2] cytokines at 2 years from [peripheral blood mononuclear cells] in T-helper-cell dependent memory responses to pertussis vaccine antigens at the birth [acellular pertussis] vaccine cohorts.”

(Wood N. Pediatr Infect Dis J. 2014;doi:10.1097/INF.0000000000000246.)

Comments

Roger Baxter

Strategies to protect infants, those who are most susceptible to severe consequences of pertussis, are complicated by poor responses to vaccines in the first months of life. Although a small study, this adds to our knowledge about early infant responses, and about the waning of acellular pertussis vaccines, which has been shown recently in multiple studies. The good news is that doses of acellular pertussis at birth and 4 weeks did not lead to a blunting of pertussis titers later on. In addition, antibody titers were higher at 2 months in those receiving an infant dose and 4-week dose, which may translate into some protection against disease. It isn’t clear how much these antibodies actually protect against disease and the benefit is very short-lived, leaving us wondering if the benefit is worth the effort, or whether the current ACIP recommendation of maternal vaccination with every pregnancy is still the best notion.

(Roger Baxter, MD; Co-Director of the Vaccine Study Center at Kaiser Permanente, Oakland, Calif, In Infectious Diseases in Children, 2014.)

Co-infection less likely among children with pneumonia serotypes

Among children with community-acquired alveolar pneumonia, those with pneumonia serotypes had lower blood sodium and hemoglobin concentrations and were less likely to be coinfected with respiratory viruses, according to data presented at ICAAC 2014.

Clinical and laboratory data for children younger than 5 years with community-acquired alveolar pneumonia was assessed by researchers from Soroka University Medical Center and Ben-Gurion University of the Negev in Beer-Sheva, Israel. The study cohort consisted of 1,423 episodes of community-acquired alveolar pneumonia. Of these, 300 had pneumonia serotypes, 591 had non-pneumonia serotypes, and 532 tested negative for pneumonia.

Nasopharyngeal carriage of pneumonia serotypes 1, 5, 7F, 14 and 19A was associated with more severe disease and presented as higher temperature, anemia and inflammatory response among children carrying Streptococcus pneumoniae serotypes, according to study researcher Ron Dagan, MD.

Ron Dagan

However, disease severity did not differ between children with S. pneumoniae serotypes and those who did not have S. pneumoniae serotypes.

Children without pneumonia serotypes or had non-pneumonia serotypes were more likely to have viral coinfections compared with children who had S. pneumoniae serotypes.

“These study findings suggest that pneumonia serotypes are more virulent, causing more severe disease and evoke a higher inflammatory response compared with non-pneumonia serotypes. Because pneumonia serotypes are more virulent, they are less dependent on previous or concurrent viral infection, as expressed by lower carriage of viruses during pneumonia associated with these serotypes,” Dagan told Infectious Diseases in Children.

(Fainguelernt Y. Abstract G-285. Presented at: 2014 Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 5-9, 2014; Washington, D.C.)

HPV4 vaccine safe, effective 8 years post-vaccination

Three doses of quadrivalent HPV vaccine provided protection against disease and persistent infection for more than 8 years, according to recent study findings.

“With the publication of these study findings, the final piece of the HPV4 vaccine puzzle has been completed. The vaccine has been established as extremely durable — for 8 years now!” said study researcher and Infectious Diseases in Children Editorial Board member Stan L. Block, MD, FAAP. “This gets the primary HPV4 vaccine target population of 11- to 12-year-old patients (and up to aged 15) almost past the age of highest risk for sexual acquisition of this toxic and complex cancer-causing virus. With certainty, data have shown that the vaccine will keep vaccinees protected beyond 19 to 23 years old. Furthermore, a 10-year duration study for HPV4 vaccinees is currently being completed.”

Stan L. Block

Daron Ferris, MD, of Georgia Regents University in Augusta, Ga., and colleagues determined serological levels and vaccine effectiveness of HPV4 (Gardasil, Merck) 8 years following vaccination. Sexually naive children aged 9 to 15 years received either HPV4 vaccine (n=1,179) or saline placebo (n=482) at day 1 and months 2 and 6. At month 30, the placebo group received HPV4 vaccine following the same regimen. Both groups were followed through month 96. Children who were aged 16 years and older were eligible for effectiveness evaluations.

None of the children who received HPV4 vaccine at a mean age of 12 years developed disease or persistent infection caused by vaccine serotypes (HPV6/11/16/18) that lasted longer than 12 months. Children who received HPV4 vaccine at month 30 (at a mean age of 15 years) had a baseline seropositivity rate to one or more of the four HPV types similar to those vaccinated at day 1 (1.7% vs. 1.9%). However, four out of nine children vaccinated at the later age were seropositive to three vaccine types, which researchers said indicated previous HPV exposure.

Children aged 16 years and older had an estimated one new sexual partner per year.

No new serious adverse events occurred 8 years post-vaccination, according to Ferris and colleagues.

“The HPV4 vaccine administered to preadolescents and adolescents demonstrated durability in clinically effective protection and sustained antibody titers over 8 years… These long-term follow-up data, along with other extensive preapproval safety surveillance data, should help to encourage practitioners and reinforce national recommendations for HPV vaccination of all preadolescents and young adolescents,” the researchers concluded.

According to Block, three milestones must be achieved for any new vaccine that prevents a serious, common disease to gain complete trust among practitioners. First is safety. More than 30 studies have carefully evaluated the safety and tolerability of HPV4 vaccine. Overall, no vaccine-related major short term or long term adverse effects have been shown, either in comparative clinical trials or in large scale population observational studies.

Second is effectiveness. HPV4 has been shown to be almost 100% effective in preventing disease for young adult and adolescent females and males by the vaccine-included strains.

“Data also shows an overall intent-to-treat effectiveness of nearly 70% to 75% in a general population on average for all pre-cancers and cancers caused by HPV. Because the three-dose post-vaccine antibody concentrations are about twofold higher in 9- to 15-year-old patients than in this older female population, this antibody surrogate marker highly suggests that HPV4 should be similarly protective in pre-teens,” Block told Infectious Diseases in Children.

Third is durability, according to Block: “Are younger vaccinated patients, aged 9 to 15 years, in need of further doses to maintain protection? The study findings show no cases of breakthrough HPV4-type disease or persistent infection (12 months or longer) in any of these 429 younger patients in this long-term follow-up study.”

Block added that physicians should inform patients and parents that HPV4 vaccination prevents cancer of four different anogenital tract cancers, and possibly for oral cancers.

“Insist that your age-appropriate patients receive the vaccine. Do not be wishy-washy in your explanations. You now have all the verbal tools you need to vaccinate all but the most ardent nay-sayers and science deniers.”

(Ferris D. Pediatrics. 2014; doi:10.1542/peds.2013-4144.)

Defective Gene Renders Diarrhoea Vaccine Ineffective in Children

Every year rotavirus causes half a million diarrhoea-related deaths amongst children in developing countries. Existing vaccines provide poor protection and the reason could be a widespread genetic resistance amongst children, according to a study published early online ahead of the print issue of the Journal of Clinical Infectious Diseases.

Acute diarrhoeal illnesses cause nearly one-fifth of all child deaths in developing countries. The most common cause is rotavirus. Improved sanitation and hygiene have had a limited effect on the spread of the illness. Today, vaccination is considered the most important method for reducing mortality.Unfortunately, several studies have shown that the 2 available living vaccines, Rotarix and RotaTeq, are not sufficiently effective in developing countries. In many African countries, protection has been as low as 20% to 50%.

In the current study, Johan Nordgren, MD, Linköping University, Linköping, Sweden, and colleagues showed that up to 4 of 10 children in Burkina Faso are genetically resistant to the virus strains found in the vaccines.The researchers found that children who cannot express a particular sugar molecule in the small intestine, called the Lewis molecule, do not become infected by the rotavirus types found in existing vaccines. This Lewis molecule is probably needed as a receptor for the rotavirus to be able to enter and infect the host cell in the intestine. This means that these children do not get the desired immunological protection from the vaccine.

The occurrence of these Lewis-negative children is small in Europe and North America, but up to 10 times higher in many African countries.The results can greatly impact the evaluation of the rotavirus vaccines now being introduced in several developing countries. The findings could lead to a review of the vaccine composition, and the development of vaccines better suited to the populations most affected by rotavirus.

(SOURCE: Linköping University)

Defective Gene Renders Diarrhoea Vaccine Ineffective in Children

Recent data show no increase in pertussis vaccination rates occurred following the 2011-2012 pertussis outbreak in Washington State.

Elizabeth R. Wolf, MD, of the Seattle Children’s Research Institute in Seattle, and colleagues compared the proportion of infants aged 3 to 8 months who were up-to-date with pertussis-containing vaccines, including diphtheria-tetanus-acellular pertussis (DTaP) and combination vaccines that contained DTaP. The investigators also recorded receipt of 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar, Pfizer) and 13-valent pneumococcal conjugate vaccine) PCV13; Prevnar 13, Pfizer) before, during and after the epidemic, which occurred from October 2011 through December 2012. According to Wolf and colleagues, this lack in increase of vaccination rates goes against conventional wisdom that vaccine acceptance uniformly increases when risk of disease is high.

Elizabeth R. Wolf

Infants in the study were enrolled in the Washington State Immunization Information System.

>Overall, 67.4% of infants were up-to-date with a pertussis-containing vaccine before the epidemic, compared with 69.5% during and 67.6% after the epidemic. The proportion of up-to-date infants was not significantly different before and during the epidemic or before and after the epidemic. Further, there was no significant difference in the proportion of infants up-to-date with pneumococcal vaccines when comparing epidemic and post-epidemic rates with pre-epidemic and post-epidemic rates.

When comparing pre-epidemic and during epidemic rates, there was no significant changes in up-to-date status with pertussis-containing vaccines beyond changes in up-to-date status with pneumococcal vaccines. However, there was a significant difference between post-epidemic and pre-epidemic time points.

Up-to-date status for pertussis-containing vaccines varied across counties; 2 counties had significant increases and 3 counties had significant decreases.

“The lack of significant change in pertussis vaccination with the 2011 to 2012 epidemic is in contrast to studies of individual health behavior that positively correlate vaccination with greater perception of disease severity and susceptibility. One possible explanation…is that the fear of vaccine-related adverse effects may have remained more influential on parental decision-making than the fear of disease,” the researchers wrote.

(Wolf ER. Pediatrics. 2014; doi:10.1542/peds.2013-3637)

Mutated PoliovirusCan Resist Vaccination

A mutated poliovirus was able to resist the protection of vaccination in victims of a large outbreak in the Congo in 2010, researchers from Germany reported.

During the outbreak, which occurred in Pointe Noire, Republic of the Congo, there were 445 confirmed cases of infection — mostly young adults — and 209 deaths. The 47% case-fatality rate was attributed to low immunization coverage, but surveys indicated that approximately half of the victims remembered receiving the full, three-dose polio vaccination series.

“We isolated polio viruses from the deceased and examined the viruses more closely,” Jan Felix Drexler, MD, of the Erasmus University Medical Center in Rotterdam, Netherlands, said in a press release. Drexler conducted the study while working at the University of Bonn. “The pathogen carries a mutation that changes its form at a decisive point.”

Drexler and colleagues isolated the wild poliovirus strain from several fatal cases, termed PV1-RC2010, and tested the pathogen in the blood samples of 34 medical students at the University of Bonn. Each student was routinely vaccinated in childhood. Results of the analysis indicated that neutralizing antibody titers against PV1-RC2010 were significantly lower than those against several vaccine-derived strains, including Sabin-1.

According to the researchers, the same pathogen could potentially have affected numerous people in Germany.

Between 15% and 29% of the medical students were unprotected against the mutated virus, despite being vaccinated against Sabin-1.

“We estimate that one in five of our Bonn test subjects could have been infected by the new polio virus, perhaps even one in three,” study researcher Christian Drosten, MD, of the Institute of Virology at the University of Bonn Medical Center, said in the release.

(Drexler JF. Proc Natl Acad Sci USA. 2014;doi:10.1073/pnas.1323502111)

Two doses of varicella vaccine more effective than one

A two-dose regimen of varicella vaccine provided more protection than a one-dose regimen among school-aged children, according to study findings in thePediatric Infectious Disease Journal.

Carrie A. Thomas, PhD, of the West Virginia Department of Health and Human Resources, Charleston. W.Va., and colleagues assessed varicella cases that occurred in West Virginia public schools between January 2010 and May 2011, alongside vaccination information from schools, health departments and health care providers in the area. During the study period, 30 varicella outbreaks and 266 cases were reported from 30 schools in 17 counties. Cases with missing information were excluded, and the final study cohort consisted of 133 children with varicella and 365 of their classmates, who served as the control, with a mean age of 11 years. Type of varicella vaccine received was not recorded.

Overall, vaccine effectiveness was 83.2% (95% CI, 69.2%-90.8%) for one dose of varicella vaccine and 93.9% (95% CI, 86.9%-97.1%) for two doses. The incremental vaccine effectiveness (defined as two doses vs. one dose) was 63.6% (95% CI, 32.6%-80.3%) against all varicella. One dose vaccination was 88.2% (95% CI, 72.7%-94.9%) effective in preventing moderate and severe varicella, compared with two dose vaccination which was 97.5% (95% CI, 91.6%-99.2%) effective. The incremental vaccine effectiveness was 78.6% (95% CI, 40.9%-92.3%) for moderate and severe varicella.

Vaccine effectiveness of the one-dose regimen decreased as time increased, from 93% effectiveness less than 5 years after vaccination to 81.8% effectiveness 10 years after vaccination.

Both regimens had milder rash than unvaccinated cases. Rash severity decreased as the number of doses decreased. The proportion of mild rash decreased from 70% among children who received two doses; 49.1% among those who received one dose; and 24.6% among those with varicella who were unvaccinated.

No severe disease was found among children who received two doses.

“In varicella school outbreaks reported during 2010 to 2011, two doses of varicella vaccine conferred greater protection against all varicella and moderate/severe varicella than a single dose. These data, in addition to declines in varicella incidence and the reduced number and size of varicella outbreaks observed since the initiation of the two-dose varicella vaccination regimen, provide evidence of the greater effectiveness of two-dose varicella vaccination compared to the single dose regimen,” the researchers concluded.

Delayed MMR, MMRV vaccination linked to seizures

Delayed receipt of measles-mumps-rubella and measles-mumps-rubella-varicella vaccines during the second year of life increases the risk for seizures, according to study findings in Pediatrics.

Simon J. Hambidge, MD, PhD, of Kaiser Permanente in Denver, and colleagues reviewed data from the Vaccine Safety Datalink, a collaborative project between the CDC and several managed care organizations across the United States, from 2004 to 2010. Researchers focused on children aged 2 to 24 months.

Of the 5,667 children included in the study, 49.7% were vaccinated on time for all vaccines during their first 2 years of life. Of children who had their first seizure at age 38 to 364 days, 71.2% were vaccinated on time. Sixty-two percent of children who had their first seizure at age 1 to 2 years were vaccinated on time.

There was no association between vaccination and seizures among children vaccinated at the age of 38 to 92 days, as recommended by the Advisory Committee on Immunization Practices. Seizures were less common in this age group overall. The incident rate ratio (IRR) for seizure occurring within 2 days of diphtheria-tetanus-acellular pertussis vaccination compared with control periods was 1.26 (95% CI, 0.65-2.45) for this age group. For children whose first vaccination was delayed between 93 days and 2 years, the IRRs for seizures were higher but insignificant; IRR for DTaP was 1.56 (95% CI, 0.19-12.92).

The researchers also reported that there was an increased risk for seizures 7 to 10 days after vaccination when the MMR vaccine (M-M-R II, Merck) was administered at the ACIP-recommended age of 12 to 15 months. The IRR was 2.65 (95% CI, 1.99-3.55). The risk for seizures increased if the MMR vaccine was received later than age 15 months, with IRR of 6.53 (95% CI, 3.15-13.53). Receipt of MMR vaccine at 16 to 18 months had an IRR of 5.09 (95% CI, 2.05-12.66). The risk for seizure after MMR vaccination was most prominent in children who received the vaccine at 19 to 21 months, with an IRR of 8.75 (95% CI, 2.35-32.58).

The MMRV vaccine (ProQuad, Merck) was associated with an increased risk for seizures 7 to 10 days after vaccination. When received at 12 to 15 months, the IRR was 2.75 (95% CI, 2.03-3.7). Risk increased with age; the IRR for seizures was 3.64 when vaccinated at 16 to 23 months, according to the study findings.

The association between vaccination and seizure was twice as high for recipients of MMRV than recipients of MMR vaccine, regardless of those who were vaccinated on time or delayed.

“Given the overall low absolute risk of seizures after MMR and MMRV vaccines, the lack of association of simple febrile seizures with long-term adverse consequences, and the known benefits of on-time vaccination, our findings provide additional rationale for not delaying childhood vaccinations,” the researchers concluded.

(Hambidge SJ. Pediatrics. 2014;doi:10.1542/peds.2013-3429.)

Hepatitis B infant immunization protects through adolescent years

A seroprotective response to a challenge dose of hepatitis B vaccine was seen in more than 90% of study participants who received the vaccine as infants, according to recent study findings published in Pediatrics.

Amy B. Middleman, MD, MSEd, MPH, anInfectious Diseases in Children Editorial Board member, and colleagues evaluated 420 adolescents aged 16 to 19 years who received a recombinant hepatitis B virus(HBV) vaccine three-dose series to determine protective titers of antibody to hepatitis B surface antigen (HBsAg) before and after a challenge dose of the vaccine. Participants were divided in to two groups, those who had the series initiation within 7 days of birth (group 1) or at 4 weeks or more following birth (group 2).

Participants in group 1 were younger, less likely to be white and less likely to have private insurance compared with group 2. Participants in group 2 were more likely to report cigarette use within the past 30 days (13%) compared with group 2 (7%; P=.019). The same was true for alcohol use (31% group 2 vs. 19% group 1; P=.0069). When examining for differences between participants who received either the 10 mcg or 20 mcg challenge dose of vaccine, none were found in demographic characteristics.

Seventy-six percent of participants had anti-hepatitis levels of less than 10 IU/mL. Nonseroprotective levels were more common in group 1 participants. Ninety-two percent of all participants achieved effective seroprotective levels following the challenge dose. Differences were not found among the groups regarding seroprotection, regardless of whether they received the 10 mcg or 20 mcg challenge dose, according to the study findings.

Group 2 had significantly higher geometric mean titers (GMTs) in response to the challenge dose compared with group 1. Participants who received the 20 mcg dose also had higher GMTs compared with the 10 mcg dose.

Higher baseline antibody to hepatitis B titer, older age at first dose of the primary series, higher test dosage, nonwhite rate, interactions of test dosage and marijuana use were independently associated with a higher GMT response to a challenge dose of vaccine.

“Given these data, together with the currently low prevalence of acute hepatitis B in the United States, the addition of a booster dose of hepatitis B vaccine to the routine immunization schedule for adolescents appears unnecessary,” The researchers wrote. “These data likely apply broadly to the continental US population at large. It will be important to follow up with a similar population 20 to 25 years after hepatitis B vaccine administration during infancy to determine duration of protection into the third decade of life.”

(Middleman AB. Pediatrics. 2014;doi:10.1542/peds.2013-2940.)