Rationally designed strings of promiscuous CD4+ T cell epitopes provide help toHaemophilus influenzae type b oligosaccharide: a model for new conjugate vaccines

Falugi, Fabiana; Petracca, Roberto; Mariani, Massimo A.; Luzzi, Enrico; Mancianti, Silvia; Carinci, Valeria; Melli, Maria Luisa; Finco, Oretta; Wack, Andreas; Tommaso, A. Di; Magistris, Maria Teresa De; Costantino, Paolo; Giudice, Giuseppe Del; Abrignani, Sergio; Rappuoli, Rino; Grandi, Guido

doi:10.1002/1521-4141(200112)31:12<3816::aid-immu3816>3.0.co;2-k

Cited by 53 publications

(36 citation statements)

References 28 publications

(33 reference statements)

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“…The peptide contains both T-and B-cell epitopes and is advantageous for eliciting an effective immune response (37). Recent studies have shown that recombinant proteins corresponding to strings of universal CD4 ϩ T-cell epitopes as carriers induced an immune response against H. influenzae, which was as good as or better than that with the licensed vaccines (38). Thus, it is essential to study T-and B-cell combined epitopes for the development of novel vaccines.…”

Section: Discussionmentioning

confidence: 99%

Serum Concentrations of Antibodies against Outer Membrane Protein P6, Protein D, and T- and B-Cell Combined Antigenic Epitopes of Nontypeable Haemophilus influenzae in Children and Adults of Different Ages

Chen

Shang

et al. 2016

Clin Vaccine Immunol

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e Nontypeable Haemophilus influenzae (NTHi) is one of the most common etiologies of acute otitis media, rhinosinusitis, and pneumonia. Outer membrane proteins (OMPs) are the main focus in new vaccine development against NTHi, as the H. influenzae type b (Hib) vaccine does not cover noncapsulated NTHi. The OMPs P6 and protein D are the most promising candidate antigens for an NTHi vaccine, and low antibody levels against them in serum may be correlated with infection caused by NTHi. In the current study, we measured the antibody titers against P6, protein D, and their T-and B-cell combined peptide epitopes in healthy individuals of different ages. We found that children <1 month old had the lowest antibody levels against NTHi P6, protein D, and their T-and B-cell combined antigenic epitopes. Antibody titers increased at ages 1 to 6 months, peaked at 7 months to 3 years, and remained high at 4 to 6 years. The antibody titers started to decrease after 6 years and were the lowest in the 21-to 30-year group. The geometric mean titers (GMTs) of T-and B-cell combined antigenic epitopes in P6 and protein D were positively correlated with those of the protein antigens. Among 12 peptides tested, P6-61, P6-123, and protein D-167 epitopes were better recognized than others in human serum. These findings might contribute to the development of an effective serotypeindependent vaccine for H. influenzae. Haemophilus influenzae is one of the normal inhabitants of the human nasopharynx and is responsible for pneumonia, acute otitis media (AOM), and acute rhinosinusitis (1-3). The presence or absence of a polysaccharide capsule segregates this bacterial species into two well-defined groups: one group of encapsulated strains and another group of noncapsulated strains, commonly referred to as nontypeable H. influenzae (NTHi) (3). Common infections caused by NTHi include otitis media in children and lower airway infections of chronic obstructive pulmonary disease in adults (4, 5). Vaccines composed of polysaccharide capsule conjugated to protein carriers have virtually eliminated infections caused by encapsulated H. influenzae type b, including meningitis and other systemic infections, in regions where the vaccines are widely administered (6, 7). However, these conjugate vaccines have no effect on infections caused by NTHi, and in regions with H. influenzae type b vaccination programs, nontypeable strains are now the most common cause of noninvasive H. influenzae infection, so that the development of the vaccine against NTHi is an urgent and challenging task (8-10).Since NTHi organisms are noncapsulated bacteria, the outer membrane proteins (OMPs) are the main targets for vaccine designers. Several research groups have identified conserved surface proteins and tested them as putative vaccines, and the conserved NTHi antigens with demonstrated preclinical protective capacity have been identified, among which P6 and protein D are the most widely studied (11)(12)(13)(14).Experimental data derived from humans and animal models indicate t...

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Section: Discussionmentioning

confidence: 99%

Serum Concentrations of Antibodies against Outer Membrane Protein P6, Protein D, and T- and B-Cell Combined Antigenic Epitopes of Nontypeable Haemophilus influenzae in Children and Adults of Different Ages

Chen

Shang

et al. 2016

Clin Vaccine Immunol

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“…Although the ability of primed uncommitted cells to help B cell responses is currently unknown, the IL-2 ϩ IFN-␥ Ϫ cells might also contribute to help for Ab production because of their higher frequency and their production of the B cell helper factor IL-2. Polysaccharide Ags can induce T cell-independent anti-polysaccharide Ab responses, but conjugation of polysaccharide Ags with carrier proteins such as diphtheria or tetanus is thought to enhance vaccination efficacy by providing T cell help, for example in children immunized with the Hib capsular polysaccharide (32,33). These results raise the possibility that in addition to B cell help provided by IL-4/IL-5-producing CD4 T cells, the generation of IL-2 ϩ IFN-␥ Ϫ CD4 memory T cells may also contribute to help for Ab responses.…”

Section: Discussionmentioning

confidence: 99%

Protein Vaccines Induce Uncommitted IL-2-Secreting Human and Mouse CD4 T Cells, Whereas Infections Induce More IFN-γ-Secreting Cells

Divekar

Zaiss

Lee

et al. 2006

The Journal of Immunology

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Mouse and human CD4 T cells primed during an immune response may differentiate into effector phenotypes such as Th1 (secreting IFN-γ) or Th2 (secreting IL-4) that mediate effective immunity against different classes of pathogen. However, primed CD4 T cells can also remain uncommitted, secreting IL-2 and chemokines, but not IFN-γ or IL-4. We now show that human CD4 T cells primed by protein vaccines mostly secreted IL-2, but not IFN-γ, whereas in the same individuals most CD4 T cells initially primed by infection with live pathogens secreted IFN-γ. We further demonstrate that many tetanus-specific IL-2+IFN-γ− cells are uncommitted and that a single IL-2+IFN-γ− cell can differentiate into Th1 or Th2 phenotypes following in vitro stimulation under appropriate polarizing conditions. In contrast, influenza-specific IL-2+IFN-γ− CD4 cells maintained a Th1-like phenotype even under Th2-polarizing conditions. Similarly, adoptively transferred OTII transgenic mouse T cells secreted mainly IL-2 after priming with OVA in alum, but were biased toward IFN-γ secretion when primed with the same OVA peptide presented as a pathogen Ag during live infection. Thus, protein subunit vaccines may prime a unique subset of differentiated, but uncommitted CD4 T cells that lack some of the functional properties of committed effectors induced by infection. This has implications for the design of more effective vaccines against pathogens requiring strong CD4 effector T cell responses.

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“…Specific antibody production is activated through a series of biochemical events inside T cells, particularly Th2, which play a major role in the production of antibodies (2,3). Nonencapsulated H. influenzae can lead to the development of a variety of acute and chronic respiratory tract diseases, such as sinusitis, bronchitis, and pneumonia, besides otitis and conjunctivitis; it is responsible for 20% -30% of otitis cases and probably a high percentage of recurrent cases (4-6).…”

Section: Introductionmentioning

confidence: 99%

Truncated D Protein as a New Vaccine Candidate Against Nontypeable Haemophilus influenza

Behrouzi

Bouzari

Oloomi

et al. 2018

Arch Pediatr Infect Dis

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Background: Nonencapsulated, nontypeable Haemophilus influenzae (NTHi) is considered an important cause of acute otitis in children and respiratory diseases among adults. The bacteria express several outer membrane proteins, some of which have been studied as vaccine candidates. Protein D is a highly conserved surface lipoprotein, which has been found in strains of both encapsulated and nonencapsulated H. influenzae. Objectives: Opsonin and protective antibodies against protein D play major roles in the prevention of infections caused by NTHi. Since NTHi can be also an intracellular organism, it needs to be removed through immune-mediated mechanisms. Methods: In this study, groups of BALB/c mice were subcutaneously immunized with recombinanat truncated D protein and an aluminum hydroxide (alum) adjuvant or protein D combined with an outer membrane vesicle (OMV) adjuvant from Neisseria meningitidis bacteria. Then, opsonophagocytic activities of antibodies were measured in serum samples collected on days 14, 28, and 42. The levels of interleukin-4 (IL-4), IL-10, and interferon-gamma were measured in splenocyte cultures of immunized mice. Results: The opsonophagocytic activity of antibodies significantly increased in the immunized mice, compared to the control group, particularly on day 42. In addition, the secretion level of cytokines significantly increased in both groups of immunized mice, compared to the control group. Conclusions:The results of this study demonstrated that recombinant truncated D protein can induce specific immune responses against nonencapsulated H. influenzae. It was suggested that the recombinant truncated D protein, as a vaccine candidate against the nonencapsulated strains of H. influenza, is essential in protection and development of sustainable immunity against infections caused by this bacterium.

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Rationally designed strings of promiscuous CD4+ T cell epitopes provide help toHaemophilus influenzae type b oligosaccharide: a model for new conjugate vaccines

Cited by 53 publications

References 28 publications

Serum Concentrations of Antibodies against Outer Membrane Protein P6, Protein D, and T- and B-Cell Combined Antigenic Epitopes of Nontypeable Haemophilus influenzae in Children and Adults of Different Ages

Serum Concentrations of Antibodies against Outer Membrane Protein P6, Protein D, and T- and B-Cell Combined Antigenic Epitopes of Nontypeable Haemophilus influenzae in Children and Adults of Different Ages

Protein Vaccines Induce Uncommitted IL-2-Secreting Human and Mouse CD4 T Cells, Whereas Infections Induce More IFN-γ-Secreting Cells

Truncated D Protein as a New Vaccine Candidate Against Nontypeable Haemophilus influenza

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