Live flu vaccine ineffective
A recent
analysis documented the lack of effectiveness of the live attenuated
influenza vaccine (LAIV) in children
during the 2015-2016 season, despite normal effectiveness of
the inactive vaccines (see DOI:
10.1056/NEJMoa1700153).
Details:
--6879 eligible people were evaluated through the Influenza Vaccine Effectiveness Network (5 sites across the US)
--5570 tested negative for flu, 1309 positive; 2668 were unvaccinated and 2902 vaccinated
--22% were 6 mo-8 yr old, 13% 9-17 yo, 35% 18-49, 17% 50-64, 13% >65; overall 30% were 2-17 yo. 75% white, 8% black, 8% Hispanic
--1309 (19%) tested positive for influenza virus (case patients): 11% had A(H1N1)pdm09 (58% of the case patients) and 7% influenza B (34% of case patients). these flu-infected patients were more likely to be 9-64 yo, male, black, have "excellent" general health, and less likely to be obese or to have gotten the flu vaccine.
--all strains of the flu that were genetically sequenced were similar to those in the vaccine (ie, the vaccine had a good match with the actual flu).
--patients with positive flu tests (by combined nasal and oropharyngeal swabs analyzed by real-time PCR) who had the vaccine were compared to those who did not have the vaccine
Results:
--overall vaccine effectiveness against any flu: 48%
--among children aged 2-17:
--inactivated influenza vaccine was 60% effective (p<0.001): 63% for A(H1N1)pdm09 and 54% for influenza B
--LAIV was ineffective, at 5% (p=0.80); the odds ratio (OR) for getting the flu was 2.7 comparing those getting LAIV vs inactivated vaccine
--specifically for influenza A(H1N1)pdm09:
--inactivated influenza vaccine was 63% effective (p<0.001)
--LAIV was ineffective, at -19% (p=0.55)
--for influenza B;
--inactivated influenza vaccine was 54% effective (p=0.001)
--LAIV was ineffective, at -18% (p=0.53)
--significant vaccine effectiveness overall was found in each age group (though limited to the inactivated trivalent or quadrivalent vaccines)
--nonsignificant trend that quadrivalent (1885 people) was better than trivalent (781 people) inactive vaccines
--no significant difference if the person had received vaccine the prior year (though B/Victoria had trend to less effectiveness if prior year vaccination; not true for B/Yamagata or A(H1N1)pdm09). [some prior studies had found diminished vaccine effectiveness if the flu vaccine had been given the prior year, for example see prior blog ]
Commentary:
--this follows a study of the 2013-14 season, where the quadrivalent LAIV was ineffective for children, despite effectiveness of the trivalent and quadrivalent inactivated vaccines
-- another study (Influenza Clinical Investigation for Children) did find a non-significant 50% vaccine effectiveness for the quadrivalent LAIV in children 2-17yo, but a significant 71% effectiveness for the inactivated vaccines. A Finnish study found significant benefit from LAIV and a UK study found insignificant benefit, but both were inferior to inactivated vaccine.
--why would the LAIV be less effective??? prior studies had found increased effectiveness of LAIV (which was anticipated, given increased efficacy overall of live vaccines, and the intranasal route of the vaccine should provide increased mucosal IgA protection, especially likely to be important given the importance of the nasal/respiratory mucosa in initiating clinical flu. The study authors posit "poor thermostability of the A(H1N1)pdm09 vaccine strain". Though it does seem to be a pretty consistent pattern…. And, even the older studies showing LAIV efficacy did not find it in those >50yo, and had significant drop-off as one reached the ripe old age of 30 or so. so, not really sure what is going on here. Of note, the quadrivalent LAIV used in the US, UK and Finland were all produced by the same manufacturer.
--the Advisory Committee on Immunization Practices recommended against using the LAIV for the 2016-17 influenza season, though the quadrivalent LAIV was still licensed in the US.
so, yet another example where apparent logic (that the live vaccine should be more immunogenic and should specifically enhance nasopharyngeal/respiratory IgA production) seems to come into conflict with reality..... This reinforces our need to be continually vigilant about assuming that our understanding of pathophysiology at the time, for example, should translate to public health or clinical interventions. As we have seen many times before by vigorously adopting low fat diets since the 1970s (which led to more obesity and diabetes), postmenopausal hormone replacement (which seems to increase short-term heart disease, at least), treating hyperhomocysteinemia with vitamins (which did nothing to prevent cardiovascular disease), etc etc.
Details:
--6879 eligible people were evaluated through the Influenza Vaccine Effectiveness Network (5 sites across the US)
--5570 tested negative for flu, 1309 positive; 2668 were unvaccinated and 2902 vaccinated
--22% were 6 mo-8 yr old, 13% 9-17 yo, 35% 18-49, 17% 50-64, 13% >65; overall 30% were 2-17 yo. 75% white, 8% black, 8% Hispanic
--1309 (19%) tested positive for influenza virus (case patients): 11% had A(H1N1)pdm09 (58% of the case patients) and 7% influenza B (34% of case patients). these flu-infected patients were more likely to be 9-64 yo, male, black, have "excellent" general health, and less likely to be obese or to have gotten the flu vaccine.
--all strains of the flu that were genetically sequenced were similar to those in the vaccine (ie, the vaccine had a good match with the actual flu).
--patients with positive flu tests (by combined nasal and oropharyngeal swabs analyzed by real-time PCR) who had the vaccine were compared to those who did not have the vaccine
Results:
--overall vaccine effectiveness against any flu: 48%
--among children aged 2-17:
--inactivated influenza vaccine was 60% effective (p<0.001): 63% for A(H1N1)pdm09 and 54% for influenza B
--LAIV was ineffective, at 5% (p=0.80); the odds ratio (OR) for getting the flu was 2.7 comparing those getting LAIV vs inactivated vaccine
--specifically for influenza A(H1N1)pdm09:
--inactivated influenza vaccine was 63% effective (p<0.001)
--LAIV was ineffective, at -19% (p=0.55)
--for influenza B;
--inactivated influenza vaccine was 54% effective (p=0.001)
--LAIV was ineffective, at -18% (p=0.53)
--significant vaccine effectiveness overall was found in each age group (though limited to the inactivated trivalent or quadrivalent vaccines)
--nonsignificant trend that quadrivalent (1885 people) was better than trivalent (781 people) inactive vaccines
--no significant difference if the person had received vaccine the prior year (though B/Victoria had trend to less effectiveness if prior year vaccination; not true for B/Yamagata or A(H1N1)pdm09). [some prior studies had found diminished vaccine effectiveness if the flu vaccine had been given the prior year, for example see prior blog ]
Commentary:
--this follows a study of the 2013-14 season, where the quadrivalent LAIV was ineffective for children, despite effectiveness of the trivalent and quadrivalent inactivated vaccines
-- another study (Influenza Clinical Investigation for Children) did find a non-significant 50% vaccine effectiveness for the quadrivalent LAIV in children 2-17yo, but a significant 71% effectiveness for the inactivated vaccines. A Finnish study found significant benefit from LAIV and a UK study found insignificant benefit, but both were inferior to inactivated vaccine.
--why would the LAIV be less effective??? prior studies had found increased effectiveness of LAIV (which was anticipated, given increased efficacy overall of live vaccines, and the intranasal route of the vaccine should provide increased mucosal IgA protection, especially likely to be important given the importance of the nasal/respiratory mucosa in initiating clinical flu. The study authors posit "poor thermostability of the A(H1N1)pdm09 vaccine strain". Though it does seem to be a pretty consistent pattern…. And, even the older studies showing LAIV efficacy did not find it in those >50yo, and had significant drop-off as one reached the ripe old age of 30 or so. so, not really sure what is going on here. Of note, the quadrivalent LAIV used in the US, UK and Finland were all produced by the same manufacturer.
--the Advisory Committee on Immunization Practices recommended against using the LAIV for the 2016-17 influenza season, though the quadrivalent LAIV was still licensed in the US.
so, yet another example where apparent logic (that the live vaccine should be more immunogenic and should specifically enhance nasopharyngeal/respiratory IgA production) seems to come into conflict with reality..... This reinforces our need to be continually vigilant about assuming that our understanding of pathophysiology at the time, for example, should translate to public health or clinical interventions. As we have seen many times before by vigorously adopting low fat diets since the 1970s (which led to more obesity and diabetes), postmenopausal hormone replacement (which seems to increase short-term heart disease, at least), treating hyperhomocysteinemia with vitamins (which did nothing to prevent cardiovascular disease), etc etc.
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