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. 2021 Apr 23:12:592731.
doi: 10.3389/fimmu.2021.592731. eCollection 2021.

Immune Response of Indian Preterm Infants to Pentavalent Vaccine Varies With Component Antigens and Gestational Age

Archana Kulkarni-Munje  1 , Nandini Malshe  2 , Sonali Palkar  2 , Aniket Amlekar  1 , Sanjay Lalwani  2 , Akhilesh Chandra Mishra  1 , Vidya Arankalle  1
Affiliations

Immune Response of Indian Preterm Infants to Pentavalent Vaccine Varies With Component Antigens and Gestational Age

Archana Kulkarni-Munje et al. Front Immunol. .

Abstract

Childhood vaccination plays critical role in protecting infants from several dreaded diseases. Of the global 15 million preterm (PT) infants with compromised immune system born annually, India contributes to >3.5 million. Generation of adequate vaccine-induced immune response needs to be ensured of their protection. Immune response of Indian PT (n = 113) and full-term (FT, n = 80) infants to pentavalent vaccine administered as per the national recommendation was studied. Antibody titers against component antigens of pentavalent vaccine, immune cells profiling (T and B cells, monocytes and dendritic cells) and plasma cytokines were determined pre- and post-vaccination. Additionally, cell-mediated recall immune responses to pentavalent antigens were evaluated after short time antigenic exposure to infant PBMCs. Irrespective of gestational age (GA), all the infants developed adequate antibody response against tetanus, diphtheria, and protective but lower antibody levels for Haemophilus influenzae type-b and hepatitis B in preterm infants. Lower (~74%) protective antibody response to pertussis was independent of gestational age. PT-infants exhibited lower frequencies of CD4 T cells/dendritic cells/monocytes, increased plasma IL-10 levels and lower proliferation of central and effector memory T cells than in term-infants. Proliferative central memory response of FT-infants without anti-pertussis antibodies suggests protection from subsequent infection. Responder/non-responder PT-infants lacked immunological memory and could be infected with Bordetella. For hepatitis B, the recall response was gestational age-dependent and antibody status-independent. Humoral/cellular immune responses of PT-infants were dependent on the type of the immunogen. Preterm infants born before 32 weeks of gestation may need an extra dose of pentavalent vaccine for long lived robust immune response.

Keywords: immune response; immunological memory; pentavalent vaccine; preterm birth; recall immune responses.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Study participant disposition. Out of 256 screened infants, parents of 193 infants gave informed consent for participation in the study. Two preterm infants from PT1 group were failed two meet inclusion criteria hence excluded from the study. Finally, 133 infants were able to complete the study.
Figure 2
Figure 2
Flow cytometry gating strategy to identify lymphocyte subsets. Representative flowcytometry dot plots from the PBMCs of one of the study participants. (A) Gating strategy used to identify T cells and B cell subsets. The lymphocytes were live gated during acquisition using the side and forward scatter dot plot display. Lymphocyte population was further discriminated on the basis of CD3 expression. CD3 positive population was used to identify CD4 and CD8 T cells. Whereas CD3 negative population was used to identify B cells and its subsets such as memory B cells and class switched/unswitched B cells, class switched memory B cells (CSMB) and unswitched memory B cells (USMB). (B) Gating strategy used to identify antigen presenting cells (mDC, pDC and Monocytes).During acquisition, with the help of side and forward scatter, cells of lymphomonocyte gate were identified and the cells from this population were further distinguished on the basis of absence of lineage markers (CD3, CD19 and CD56). Lineage negative population was further discriminated as CD14+ and CD14- population to identify monocyte population. CD14 negative population was again distinguished on the basis of HLA-DR expression. Both positive (CD11c and CD1C) population from HLA-DR positive cells was identified as myeloid Dendritic Cells (mDC). Plasmacytoid dendritic cells (pDC) were identified as HLA-DR+CD11C−CD123 + cells. In infants with high NRBC (nucleated RBC) count, contour plot was used to identify lymphocyte gate for further analyses.
Figure 3
Figure 3
Antibody titers against component antigens of pentavalent vaccine. The vertical scatter dot plots present antibody titers against (A) Tetanus (anti-Ttx), (B) Diphtheria (anti-Dtx) toxoids, (C) anti-PRP (HiB), (D) anti-Pertussis toxin (Bordetella) before (at baseline) and after pentavalent vaccination. Dotted lines in the graph indicate seroprotective antibody titers. Error bars- Mean with SEM.
Figure 4
Figure 4
Effect of administration of Hepatitis B Vaccine dose at birth on anti-HBs titers at pre and post pentavalent vaccination. Hepatitis B vaccine birth dose is administered to infants weighing ≥ 2000 g. Pre (baseline) and post-pentavalent vaccination anti-HBs titers are depicted with respect to the administration of birth dose: (A) (Irrespective of birth dose), (B) (no birth dose administered) and (C) (birth dose administered). The vertical scatter dot plots in the figure represent the antibody titers against HBsAg at pre and post pentavalent visits. Dotted line in the graph indicates the seroprotective antibody titers. Error bars- Mean with SEM.
Figure 5
Figure 5
Frequency of major Immune cells in PT1, PT2 and FT infant groups prior to (at baseline) and one month post-pentavalent vaccination. The vertical scatter dot plots represent frequencies of different immune cells before and after pentavalent vaccination: (A) CD4 T cells, (B) CD8 T cells, (C) CD4/CD8 T cell ratio (D) Myeloid dendritic cells, (E) Plasmacytoid Dendritic Cells and (F) monocytes. Error bars- Mean with SEM.
Figure 6
Figure 6
Plasma cytokine levels in PT1, PT2 and FT infants prior to (A) and post-(B) pentavalent vaccination. The vertical column bar graphs represent A1] Th1 cytokines (IFN-γ, IL-2, TNF-α), A2] Th2 cytokines (IL-4, IL-5, IL-6, IL-10, IL-13) and A3] Th17 and miscellaneous cytokines before vaccination; B1, B2, and B3 plots present respective cytokines at post-pentavalent vaccination. (C) The line graphs denote the changes in plasma IL-4, IL-17, IL-21, and TNF-α levels in all the infant groups before and after pentavalent vaccination. Error bars- Mean with SEM.
Figure 7
Figure 7
Fold changes in functional parameters of immune cells following individual pentavalent component antigenic stimulation of cultured PBMCs. Bar diagrams in the figure exhibit the fold rise in frequency of immune cells and expression of different markers after short term exposure to (A) Bordetella (Whole cell) (B) HBsAg (C) Haemophilus Influenzae B (PRP) in all study groups. The major memory T cell types are mentioned above the lines. Fold rise in relevant parameters are shown in boxes. In recall response analyses, PBMCs of infants without any stimulation were used as controls. The cellular frequency and their phenotypic and functional characteristics obtained in unstimulated PBMCs were considered as baseline values to estimate fold changes induced by stimulation with component antigens of pentavalent vaccine. [Concentration of antigens used for stimulation-(Tetanus toxoid (3.3 LF/ml), Diphtheria toxoid (2.4 LF/ml, PRP of Hib, 1 µg/ml), HBs Ag (1 µg/ml) and the whole cell of pertussis (0.18 IOU/ml); Incubation time, 6 h]. As against significant rise (>1.5 fold) of all the indicated markers in the FT group, PT1 documented 2.06 fold (Bordetella: central memory CD8 T cells, CD300a MFI) and 2.35 fold (HiB: TNF-α, and IFN-γ bifunctional central memory CD8 T cells). In PT2 infants, 2.2 fold (Bordetella: central memory CD8 T cells, CD300a MFI), 1.5 fold (HBsAg: central memory CD8 T cells, TNF-α MFI, and BCMA+ plasma cells) and 2.33 fold (HiB: central memory CD8 T cells, CD300a MFI).
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