Since 1978, the annual influenza vaccine contained three strains — two influenza A strains and one influenza B strain. This year, a number of quadrivalent influenza vaccines will be added to the list of options.
“One of the problems that we’ve had with the trivalent vaccine is that it only covers one of the two influenza B lineages that can circulate or co-circulate in any given influenza season,” said Pedro A. Piedra, MD, a professor in the department of molecular virology and microbiology and pediatrics at Baylor College of Medicine. “It is difficult to predict which of the influenza B lineages will circulate in a given year. The quadrivalent influenza vaccine (QIV) eliminates that because it ensures that both B lineages are present in the vaccine, as well as both A subtypes, the A(H3N2) and the A(H1N1).”
Infectious Diseases in Children spoke with experts in the field about what this year’s influenza season may bring and the options for prevention and treatment of influenza infection.
The first-ever QIV (FluMist Quadrivalent, MedImmune) was approved in February; followed by Fluarix Quadrivalent (GlaxoSmithKline); Fluzone Quadrivalent (Sanofi-Pasteur); and FluLaval (GlaxoSmithKline).
The vaccines will include the following strains: A/California/7/2009 (H1N1)-like virus; A(H3N2) virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011; B/Massachusetts/2/2012-like virus (B Yamagata lineage); and B/Brisbane/60/2008-virus
(B Victoria lineage).
Kathleen M. Neuzil, MD, MPH, of PATH,
said adding another influenza B strain
will make the gamble of choosing influenza
vaccine strains a little “less risky.”
Photo courtesy of Neuzil K
FluMist Quadrivalent will be the only live-attenuated influenza vaccine (LAIV) and is indicated for use in healthy, non-pregnant patients aged 2 to 49 years. Fluarix and FluLaval Quadrivalent are inactivated vaccines indicated for use in patients aged at least 3 years. Fluzone Quadrivalent is another inactivated vaccine that is approved for use in all patients aged at least 6 months. This is the only quadrivalent vaccine approved for use in children aged 6 to 23 months.
Kathleen M. Neuzil, MD, MPH, director of vaccine access and delivery at PATH in Seattle, said there is evidence that B strains of influenza cause significant morbidity, and if a vaccine can cover strains more broadly, it makes the gamble “a little less risky.”
“If we have a predominant A strain circulating in a season, having that extra B in there isn’t going to make much of a difference,” Neuzil said. “Most years, you have at least some B, some years you have both lineages circulating. Overall, the QIV is very positive for public health, but exactly what will happen on a year-to-year basis is unpredictable depending on what strains end up circulating.”
Manjusha J. Gaglani, MD, who is Scott & White Healthcare’s Principal Investigator for CDC’s US Flu Vaccine Effectiveness Network, said she believes that the QIV will be helpful based on evidence from prior influenza seasons when B lineage has been mismatched more than half of the time.
“We have not been able to control influenza B epidemics very well,” Gaglani said. “I expect that we will have better effectiveness with the QIV for B strains.”
Live attenuated vs. inactivated vaccines
Trivalent and quadrivalent vaccines are licensed and will be available for the upcoming season, but neither formulation is preferred over the other, according to Neuzil.
“The influenza vaccine is unique. We have many more choices than we do for any other vaccine, and what we’re trying to do is find out what the best vaccines are for certain age groups,” she said. “That’s not always easy because we generally look at vaccine efficacy for a single year or 2 years, but we know that influenza changes and the answer one year might not be the same as the answer the next. I’m going to keep emphasizing that getting any influenza vaccine is better than no influenza vaccine.”
However, Piedra, an Infectious Diseases in Children Editorial Board member, said when compared head-to-head with the trivalent inactivated influenza vaccine, the trivalent LAIV tended to be more effective in young children.
“The LAIV is only approved for children 2 years of age or older, and it’s primarily for healthy children, so that means that for children under 2 years, the preferred vaccine, and the only vaccine, would be the inactivated influenza vaccine,” he said. “Likewise, if you had a high-risk medical condition, you would want to receive the inactivated influenza vaccine; that’s the one that’s recommended.”
According to Gaglani, school-based immunization programs with LAIVs could reduce doctor visits compared with those communities without school-based programs.
“I’m saying up to 20% or so less doctor visits for acute respiratory illness during an influenza outbreak as compared to those communities where there might not be school-based programs,” she said. “If you have school-based vaccination programs where you go and reach out to the community and vaccinate with LAIV and inactivated influenza vaccine at schools during school hours, it provides almost immediate protection.”
She said, in the past, the trivalent LAIV has provided broader protection against drifted variants in children and the duration of protection may be more than 1 year; the recommendation is to receive a vaccine each year because “vaccine strains almost always change with influenza.”
Although the LAIV may be better for young children, it is not indicated for use in high-risk children.
“We still have to vaccinate everybody because the high-risk kids are the ones who are going to end up in the hospital or ED if they don’t get vaccinated,” Gaglani said.
A number of randomized controlled trials have shown good efficacy of the trivalent LAIV in young children, according to Alicia Fry, MD, medical officer in the influenza division at the CDC’s National Center for Immunization and Respiratory Diseases.
“There is varying effectiveness for the LAIVs in children, between 60% and 80% for well-matched seasons,” Fry said. “There are limited data from randomized controlled trials with the inactivated influenza vaccine in children, which we used to call the trivalent inactivated influenza vaccine, but efficacy was similar for well-matched seasons. The data available suggest LAIV may have some additional benefits in young children compared to the inactivated influenza vaccine; however, inactivated influenza vaccine also protects children against influenza and for many children inactivated influenza vaccine may be the only vaccine available.”
Efficacy of quadrivalent LAIV
Leonard R. Krilov, MD, FAAP, chief of pediatric infectious disease at Winthrop University Hospital, Mineola, N.Y., cited a study he participated in with colleagues that examined the effectiveness of a quadrivalent LAIV compared with a trivalent LAIV. The researchers found that the quadrivalent vaccine was noninferior to the trivalent in children aged 2 to 17 years.
“The assessment was not a true efficacy or effectiveness study. We looked at seroconversion or antibody response as a marker but were able to show that there was improved response to the so-called mismatched B strain in the quadrivalent vaccine to the trivalent influenza vaccine,” he said. “There were good responses in the quadrivalent vaccine to all four strains and no less to the trivalent vaccine for those that were included.”
Pedro A. Piedra
Krilov said there were no new serious adverse effects seen with administration of the QIV. However, he does not recommend that people wait to get the QIV.
“The advisory guidelines of the [Advisory Committee on Immunization Practices] and AAP do not recommend any vaccine over the other. Pending further data, that’s appropriate,” he said. “Although as described, QIV may provide additional protection over [trivalent inactivated influenza vaccine], delaying vaccination until QIV is available would be a big mistake.”
Changes in vaccination recommendations
This year, ACIP made few changes to recommendations regarding QIV. Those aged at least 6 months are still recommended to receive influenza vaccination. According to summary recommendations released by the CDC and ACIP, “within approved indications and recommendations, no preferential recommendation is made for any type or brand of licensed influenza vaccine over another.”
Children aged 6 months to 8 years are also recommended to receive two doses of the influenza vaccine, with 4 or more weeks in between doses, the first year they are immunized against influenza.
“The argument is that when they first get the vaccine, those young children haven’t had a lot of exposure or infection with influenza, so to start building an immunity, the second dose boosts or gives an increase response compared to a single dose,” Krilov said. “That’s only the first year they get the vaccine, or if they hadn’t had two doses total previously.”
Other new ACIP recommendations included modification of the egg allergy algorithm to include recombinant hemagglutinin vaccine and a trivalent formulation, and language to address those with no history of egg exposure but questionable egg allergy testing.
The modification of the egg allergy algorithm includes offering the recombinant influenza vaccine to adults aged 18 to 49 years with egg allergies who have hives and also for those with symptoms of severe or life-threatening allergy other than hives.
Language addressing those with no history of egg exposure recommends that those with questionable egg allergy testing consult a physician with expertise in the management of allergies before vaccination.
2012-2013 influenza season
As of July 13, 154 laboratory-confirmed influenza-associated pediatric deaths were reported to the CDC for the 2012-2013 influenza season. Influenza A lineages dominated overall, particularly A(H3N2). Last year accounted for the most pediatric deaths associated with influenza since the 2009 to 2010 pandemic. Eighty-one of all pediatric deaths were associated with a B lineage; 34 with an unknown influenza A subtype; 32 with influenza A H3N2; four with A H1N1; two with both A and B lineages; and one with an undetermined type. However, most of the deaths occurred in children unimmunized against influenza.
According to Gaglani, last year’s influenza season was moderately severe, and the vaccines were effective, overall.
“As expected, we saw a reduction of over 50% in medical visits for laboratory-confirmed influenza-associated illnesses. However, the effectiveness was not as good with the A(H3N2) variant,” she said.
Transmission of H7N9
On April 1, WHO was notified of human infection with a new avian influenza A(H7N9) virus, and since then, more than 130 cases have been reported. However, there has been limited evidence of human-to-human transmission.
“The fact that we’ve already had an outbreak makes H7N9 a big concern because of certain things we know about the virus,” Fry said. “Right now, it seems very much like the H5N1, in that it causes severe illness but that it’s not very transmissible from human-to-human.”
The CDC and WHO are continuously monitoring H7N9 for any new infections or human-to-human transmissions.
“It seems to be limited, and the areas in China where it occurred have since had a decrease in reported cases,” Krilov said. “Hopefully, it’s just a local phenomenon that can be controlled. There has been much better early reporting and public health infrastructure and collaboration with WHO, which may help control the spread.”
Krilov said, since April, there strain has been cloned, there are already diagnostics developed for this virus, and potential for vaccine development exists.
“The thing about H7N9 that I find encouraging is that we are at least learning from past pandemics about better attention to public health, and that may help control outbreaks in the future,” he said.
However, this is the time of the year when not a lot of activity is seen with H7N9.
“Although there is limited action with H7N9 now, we have seen a pattern when, during influenza seasons or different times of year, even avian viruses have a bit of seasonality,” Neuzil said. “It’s hard to know where this one is going to go. It absolutely deserves the attention and caution that it’s receiving, but there’s no time for panic. It’s not the time to panic yet.” – by Amber Cox
AAP Committee on Infectious Diseases. Pediatrics. 2013;doi:10.1542/peds.2013-2377.
Block SL. Pediatr Infect Dis J. 2013;31:745-751.
CDC. MMWR. 2013;62:119-123.
CDC. MMWR. 2013:62:124-130.
CDC. Summary Recommendations: Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - (ACIP) - United States, 2013-2014. Available at: www.cdc.gov/flu/professionals/acip/2013-summary-recommendations.htm. Accessed Aug. 14, 2013.
For more information:
Alicia Fry, MD, can be reached at firstname.lastname@example.org.
Manjusha J. Gaglani, MD, can be reached at email@example.com.
Leonard R. Krilov, MD, FAAP, can be reached at Winthrop University Hospital, 120 Mineola Blvd., Suite 210, Mineola, NY 11501; email: firstname.lastname@example.org.
Kathleen M. Neuzil, MD, MPH, can be reached at 2201 Westlake Ave., Suite 200, Seattle, WA 98121; email: email@example.com.
Pedro A. Piedra, MD, can be reached at Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030; email: firstname.lastname@example.org.
Disclosures: Fry, Gaglani, Krilov and Neuzil report no relevant financial disclosures. Piedra reports being a member of the speakers bureau for MedImmune.
Should LAIV be used in all otherwise healthy children vs. the IIV?
LAIV safety and effectiveness warrants preference over IIV.
S. Elizabeth Williams
Live-attenuated influenza vaccine (LAIV) is superior to inactivated influenza vaccine (IIV) in protecting children from influenza and, therefore, should be the first choice for influenza vaccination in all otherwise healthy children older than 24 months. For the 2013-14 influenza season, LAIV will provide protection against four flu viruses: influenza A viruses H1N1 and H3N2, and two influenza B viruses. Although influenza vaccine effectiveness can vary each year depending on the appropriateness of match to the circulating viral strains, several studies that compare the effectiveness of LAIV vs. IIV in preventing influenza support that LAIV provides much greater protection for children of all ages. The first randomized control trial published in 2003 reported that culture-confirmed influenza was 53% (95% CI, 22-72) less likely to occur among LAIV recipients compared with IIV recipients (Ashkenazi S. Pediatr Infect Dis J. 2006;25:870-879). Hoft and colleagues (J Infect Dis. 2011;204:845-853) reported that only LAIV was found to induce CD4+, CD8+ and gamma delta T cells, which are relevant for broadly protective influenza immunity. Further, evidence suggests a decrease in the incidence of acute otitis media after LAIV administration, one of the most common diagnoses resulting in medical evaluation and treatment in childhood (Heikkinen T. Pediatr Infect Dis J. 2013;32:669-674). Finally, LAIV has also been demonstrated to be very safe in post-licensure studies. Toback and colleagues (Vaccine. 2013;31:1812-1818) conducted a prospective cohort study evaluating the safety of LAIV in children aged 24 to 59 months; children with a history of asthma or significant chronic medical conditions were excluded. Results demonstrated no significant increase in asthma or wheezing or other adverse outcomes among eligible children aged 24 to 59 months who received LAIV as compared with IIV recipients.
S. Elizabeth Williams, MD, MPH, is with the Department of Pediatrics at Vanderbilt University Medical Center. Disclosure: Williams reports no relevant financial disclosures.
Antibody levels lowered following LAIV.
Both inactivated (IIV) and live-attenuated influenza vaccines (LAIV) are highly safe and effective immunizations against influenza disease in children. Hospitalization rates and outpatient visits for children with influenza are among the highest of any age group (Poehling KA. N Engl J Med. 2006;355:31-40), so US advisory bodies recommended immunization of all children greater than 6 months of age in 2006 (ACIP. MMWR Recomm Rep. 2006;55:1-42). An early trial demonstrated that IIV and LAIV were both highly immunogenic and effective in young children (Edwards KM. J Infect Dis. 1994;169:68-76). Follow-up studies demonstrated that LAIV was more effective than IIV (Ashkenazi S. Pediatr Infect Dis J. 2006;25:870-879; Fleming DM. Pediatr Infect Dis J. 2006;25:860-869); however, additional studies of safety revealed that young children given LAIV had more frequent of episodes of wheezing (Bergen R. Pediatr Infect Dis J. 2004;23:138-144). Because of these findings, a large randomized, controlled, double-blinded study of 8,352 children in 16 countries was conducted to formally evaluate LAIV versus IIV (Belshe RB.N Engl J Med. 2007;356:685-696). Children in the study were between 6 and 59 months of age with no recent episodes of wheezing illness or severe asthma. While children who received LAIV had 54.9% fewer cases of culture-confirmed influenza compared to children who received inactivated vaccine, children who received LAIV were more likely to be hospitalized during the 180 days after vaccination. Among previously unvaccinated children, wheezing within 42 days after the administration of the first dose was more common with LAIV vaccine than with IIV. Combined with data that demonstrate lower antibody titers in children with repeated yearly doses of LAIV compared to the titers after the first dose of LAIV (Bernstein DI. Pediatr Infect Dis J. 2003;22:28-34), these studies suggest that inactivated vaccines are the safest and most effective influenza vaccines for otherwise healthy children.
Elizabeth P. Schlaudecker, MD, MPH, is with Vanderbilt University Medical Center. Disclosure: Schlaudecker reports no relevant financial disclosures.