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. 2016 Apr 15:7:142.
doi: 10.3389/fimmu.2016.00142. eCollection 2016.

Immune Responses to Circulating and Vaccine Viral Strains in HIV-Infected and Uninfected Children and Youth Who Received the 2013/2014 Quadrivalent Live-Attenuated Influenza Vaccine

Adriana Weinberg  1 , Donna Curtis  1 , Mariangeli Freitas Ning  1 , David Jeremy Claypool  1 , Emilie Jalbert  1 , Julie Patterson  1 , Daniel N Frank  2 , Diana Ir  2 , Carl Armon  3
Affiliations

Immune Responses to Circulating and Vaccine Viral Strains in HIV-Infected and Uninfected Children and Youth Who Received the 2013/2014 Quadrivalent Live-Attenuated Influenza Vaccine

Adriana Weinberg et al. Front Immunol. .

Abstract

The live-attenuated influenza vaccine (LAIV) has generally been more efficacious than the inactivated vaccine in children. However, LAIV is not recommended for HIV-infected children because of insufficient data. We compared cellular, humoral, and mucosal immune responses to the 2013-2014 LAIV quadrivalent (LAIV4) in HIV-infected and uninfected children 2-25 years of age (yoa). We analyzed the responses to the vaccine H1N1 (H1N1-09), to the circulating H1N1 (H1N1-14), which had significant mutations compared to H1N1-09 and to B Yamagata (BY), which had the highest effectiveness in 2013-2014. Forty-six HIV-infected and 56 uninfected participants with prior influenza immunization had blood and nasal swabs collected before and after LAIV4 for IFNγ T and IgG/IgA memory B-cell responses (ELISPOT), plasma antibodies [hemagglutination inhibition (HAI) and microneutralization (MN)], and mucosal IgA (ELISA). The HIV-infected participants had median CD4+ T cells = 645 cells/μL and plasma HIV RNA = 20 copies/mL. Eighty-four percent were on combination anti-retroviral therapy. Regardless of HIV status, significant increases in T-cell responses were observed against BY, but not against H1N1-09. H1N1-09 T-cell immunity was higher than H1N1-14 both before and after vaccination. LAIV4 significantly increased memory IgG B-cell immunity against H1N1-14 and BY in uninfected, but not in HIV-infected participants. Regardless of HIV status, H1N1-09 memory IgG B-cell immunity was higher than H1N1-14 and lower than BY. There were significant HAI titer increases after vaccination in all groups and against all viruses. However, H1N1-14 MN titers were significantly lower than H1N1-09 before and after vaccination overall and in HIV-uninfected vaccinees. Regardless of HIV status, LAIV4 increased nasal IgA concentrations against all viruses. The fold-increase in H1N1-09 IgA was lower than BY. Overall, participants <9 yoa had decreased BY-specific HAI and nasal IgA responses to LAIV4. In conclusion, HIV-infected and uninfected children and youth had comparable responses to LAIV4. H1N1-09 immune responses were lower than BY and higher than H1N1-14, suggesting that both antigenic mismatches between circulating and vaccine H1N1 and lower immunogenicity of the H1N1 vaccine strain may have contributed to the decreased H1N1 effectiveness of 2013-2014 LAIV4.

Keywords: ELISPOT; HIV infection; LAIV; cell-mediated immunity; children; influenza vaccine; neutralization.

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Conflict of interest statement

The authors do not have a commercial or other association that might pose a conflict of interest.

Figures

Figure 1
Figure 1
T-cell responses to LAIV4 measured by ELISPOT. The data were derived from 45 HIV-infected and 55 uninfected individuals. (A) Absolute responses in each group of participants, as indicated below the abscissa, at V1 (before vaccination) and V4 (14–21 days after vaccination) and against the viruses indicated in the labels of the abscissa. Asterisks (*) indicate significant differences between pre- and post-vaccination. Hash tags (#) indicate significant differences between H1N1-09 and H1N1-14. And symbols (&) indicate significant differences between HIV-infected and uninfected participants. (B) Fold-increases from pre- to post-vaccination. Asterisks (*) indicated significant differences between H1N1-09 and BY.
Figure 2
Figure 2
IgG memory B-cell responses to LAIV4 measured by ELISPOT. The data were derived from 45 HIV-infected and 55 uninfected individuals. (A) Absolute responses in each group of participants, as indicated below the abscissa, at V1 (before vaccination) and V4 (14–21 days after vaccination) and against the viruses indicated in the labels of the abscissa. Asterisks (*) indicate significant differences between pre- and post-vaccination. Hash tags (#) indicate significant differences between H1N1-09 and H1N1-14. And symbols (&) indicate significant differences between HIV-infected and uninfected participants. (B) Fold-increases from pre- to post-vaccination. Asterisks (*) indicated significant differences between H1N1-09 and BY.
Figure 3
Figure 3
Antibody responses to LAIV4 measured by HAI. The data were derived from 45 HIV-infected and 55 uninfected individuals. (A) Absolute responses in each group of participants, as indicated below the abscissa, at V1 (before vaccination) and V4 (14–21 days after vaccination) and against the viruses indicated in the labels of the abscissa. Asterisks (*) indicate significant differences between pre- and post-vaccination. (B) Fold-increases from pre- to post-vaccination. There were no significant differences across viruses or by HIV status.
Figure 4
Figure 4
Neutralizing antibody responses to LAIV4. The data were derived from 45 HIV-infected and 55 uninfected individuals. (A) Absolute responses in each group of participants, as indicated below the abscissa, at V1 (before vaccination) and V4 (14–21 days after vaccination) and against the viruses indicated in the labels of the abscissa. Asterisks (*) indicate significant differences between pre- and post-vaccination. Hash tags (#) indicate significant differences (p < 0.05) and strong trends (0.05 ≤ p < 0.1) between H1N1-09 and H1N1-14. (B) Fold-increases from pre- to post-vaccination.
Figure 5
Figure 5
Nasal IgA antibody responses to LAIV4 measured by ELISA. The data were derived from 45 HIV-infected and 55 uninfected individuals. (A) Absolute responses in each group of participants, as indicated below the abscissa, at V1 (before vaccination) and at the maximum response, which was V3 (7–10 days after vaccination) for H1N1 viruses and V4 (14–21 days after vaccination) for BY. The viruses are indicated in the labels of the abscissa. Asterisks (*) indicate significant differences between pre- and post-vaccination. And symbols (&) indicate significant differences between HIV-infected and uninfected participants. (B) Fold-increases from pre- to post-vaccination. Asterisks (*) indicated significant differences between H1N1-09 and BY.
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Grants and funding

This study was supported by MedImmune through an Investigator-Initiated Study grant to AW. This work was conducted under IND 15564.