IC31<sup>®</sup>, a Two‐Component Novel Adjuvant Mixed with a Conjugate Vaccine Enhances Protective Immunity against Pneumococcal Disease in Neonatal Mice

Olafsdottir, Thorunn A.; Lingnau, Karen; Nagy, Eszter; Jónsdóttir, Ingileif

doi:10.1111/j.1365-3083.2008.02225.x

Cited by 43 publications

(21 citation statements)

References 37 publications

(60 reference statements)

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“…No protection was observed when IC31 was reduced to 15.75 nmol KLK and 0.63 nmol ODN1a (approximately one-sixth of the adult dose). This is in contrast to our results for neonatal immunization with PCV, where the lowest dose (15.75 nmol KLK and 0.63 nmol ODN1a) of IC31 resulted in protection levels similar to those found when the highest dose (90 nmol KLK and 3.6 nmol ODN1a) was used in combination with proteins, with the latter inducing even higher vaccine-specific Ab levels (31). This finding suggests that higher levels of protein-specific Abs than PPS-specific Abs may be required to provide full protection against pneumococcal disease, possibly due to less exposure of the proteins on the bacterial surface than the PPS.…”

Section: Fig 3 Ic31 Induces Higher and More Rapid Ab Responses To Allcontrasting

confidence: 56%

“…Results from human trials of IC31 showed that when combined with the TB vaccine candidate Ag85B-ESAT6, it was well tolerated and highly immunogenic, with strong Th1 responses persisting more than 2.5 years following vaccination (48). We have previously shown that IC31 enhances the murine neonatal Ab response to a monovalent PCV and improves protection against pneumonia and lung infection (31).…”

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confidence: 99%

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Novel Protein-Based Pneumococcal Vaccines Administered with the Th1-Promoting Adjuvant IC31 Induce Protective Immunity against Pneumococcal Disease in Neonatal Mice

et al. 2012

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Streptococcus pneumoniae is responsible for many vaccine-preventable deaths, annually causing around 1 million deaths in children younger than 5 years of age. A new generation of pneumococcal vaccines based on conserved proteins is being developed. We evaluated the immunogenicities and protective efficacies of four pneumococcal protein vaccine candidates, PcsB, StkP, PsaA, and PspA, in a neonatal mouse model. Mice were immunized three times and challenged intranasally with virulent pneumococci. All four proteins were immunogenic in neonatal mice, and antibody (Ab) responses were significantly enhanced by the novel adjuvant IC31, which consists of an antibacterial peptide (KLKL 5 KLK) and a synthetic oligodeoxynucleotide, ODN1a, that signals through Toll-like receptor 9 (TLR9). Two single proteins, StkP and PspA, combined with IC31 significantly reduced pneumococcal bacteremia but had no effects on lung infection. Three proteins, PcsB, StkP, and PsaA, were evaluated with alum or IC31. IC31 enhanced Ab responses and avidity to all three proteins, whereas alum enhanced Ab responses and avidity to StkP and PsaA only. Mice receiving the trivalent protein formulation with IC31 had significantly reduced bacteremia and lung infection compared to unvaccinated mice, but the level of protection was dependent on the dose of IC31. When PspA was added to the trivalent protein formulation, the dose of IC31 needed to obtain protective immunity could be reduced. These results demonstrate that a novel pneumococcal protein-based vaccine is immunogenic at an early age of mice and emphasize the benefits of using a combination of conserved proteins and an effective adjuvant to elicit potent protective immunity against invasive pneumococcal disease. Streptococcus pneumoniae, or the pneumococcus, can cause lifethreatening invasive diseases (meningitis and bacteremia) and pneumonia and frequently causes otitis media in children. The pneumococcus remains a major cause of vaccine-preventable deaths. Current vaccines are based on capsular polysaccharides (PSs), which are a major virulence factor and the basis for the classification of pneumococci into more than 90 different serotypes. Therefore, the effect of a polysaccharide-based vaccine is restricted to the serotypes included in the vaccine, and the coverage varies due to different geographical serotype distributions (13). The pneumococcal PS (PPS) vaccine contains purified PSs of 23 serotypes (PPV23) that account for 85 to 90% of invasive disease in adults in the United States. However, PSs are not immunogenic in children Ͻ2 years of age (8, 16, 18) and do not induce immunological memory (26). These limitations were overcome by conjugating pneumococcal PS to proteins, converting the PSs from T-cell-independent (TI) to T-cell-dependent (TD) antigens (Ags) (37) that elicit immune responses in infants and induce immunological memory, affinity maturation, and isotype switching of antibodies (Abs). The seven-valent pneumococcal conjugate vaccine (PCV7), which contains 7 PPS conjugated to a ...

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Section: Fig 3 Ic31 Induces Higher and More Rapid Ab Responses To Allcontrasting

confidence: 56%

mentioning

confidence: 99%

Novel Protein-Based Pneumococcal Vaccines Administered with the Th1-Promoting Adjuvant IC31 Induce Protective Immunity against Pneumococcal Disease in Neonatal Mice

et al. 2012

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“…In April 2011 Menectra was approved for use in infants over the age of 9 months but is not yet recommended by the CDC. Hence, well-tolerated effective adjuvants may enhance and accelerate immune responses to conjugate vaccines in neonates and infants (24,25,38), the age group most vulnerable to meningococcal disease. Mycobacterium bovis bacillus Calmette-Guérin (BCG) is administered to human neonates in many countries worldwide.…”

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confidence: 99%

Concomitant Administration of Mycobacterium bovis BCG with the Meningococcal C Conjugate Vaccine to Neonatal Mice Enhances Antibody Response and Protective Efficacy

Brynjólfsson

Bjarnarson

Mori

et al. 2011

Clin Vaccine Immunol

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Mycobacterium bovis BCG is administered to human neonates in many countries worldwide. The objective of the study was to assess if BCG could act as an adjuvant for polysaccharide-protein conjugate vaccines in newborns and thereby induce protective immunity against encapsulated bacteria in early infancy when susceptibility is high. We assessed whether BCG could enhance immune responses to a meningococcal C (

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“…CpG, a TLR9 agonist, can induce adult-like DC and T-cell activation, while failing to induce adult-like antibody (Ab) responses (22). IC31 (Intercell AG), a two-component adjuvant consisting of an antibacterial peptide and the TLR9 agonist ODN1a, when combined with a pneumococcal conjugate vaccine, enhances protective immunity in neonatal mice (23). A synthetic water-in-oil emulsion-based adjuvant, CRL-8941 (24), and complete Freund's adjuvant (CFA) (25), induced adult-like T H 1 immune responses in neonatal mice, indicated by induction of antigen-specific IgG2a antibodies (an indicator of a T H 1 response in BALB/c mice) and/or IFN-␥-secreting splenocytes.…”

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confidence: 99%

An Alphavirus-Based Adjuvant Enhances Serum and Mucosal Antibodies, T Cells, and Protective Immunity to Influenza Virus in Neonatal Mice

Khalil

Tonkin

Snead

et al. 2014

J Virol

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Neonatal immune responses to infection and vaccination are biased toward T H 2 at the cost of proinflammatory T H 1 responses needed to combat intracellular pathogens. However, upon appropriate stimulation, the neonatal immune system can induce adult-like T H 1 responses. Here we report that a new class of vaccine adjuvant is especially well suited to enhance early life immunity. The GVI3000 adjuvant is a safe, nonpropagating, truncated derivative of Venezuelan equine encephalitis virus that targets dendritic cells (DCs) in the draining lymph node (DLN) and produces intracellular viral RNA without propagating to other cells. RNA synthesis strongly activates the innate immune response so that in adult animals, codelivery of soluble protein antigens induces robust humoral, cellular, and mucosal responses. The adjuvant properties of GVI3000 were tested in a neonatal BALB/c mouse model using inactivated influenza virus (iFlu). After a single immunization, mice immunized with iFlu with the GVI3000 adjuvant (GVI3000-adjuvanted iFlu) had significantly higher and sustained influenza virus-specific IgG antibodies, mainly IgG2a (T H 1), compared to the mice immunized with antigen only. GVI3000 significantly increased antigen-specific CD4؉ and CD8 ؉ T cells, primed mucosal immune responses, and enhanced protection from lethal challenge. As seen in adult mice, the GVI3000 adjuvant increased the DC population in the DLNs, caused activation and maturation of DCs, and induced proinflammatory cytokines and chemokines in the DLNs soon after immunization, including gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), granulocyte colony-stimulating factor (G-CSF), and interleukin 6 (IL-6). In summary, the GVI3000 adjuvant induced an adult-like adjuvant effect with an influenza vaccine and has the potential to improve the immunogenicity and protective efficacy of new and existing neonatal vaccines. IMPORTANCEThe suboptimal immune responses in early life constitute a significant challenge for vaccine design. Here we report that a new class of adjuvant is safe and effective for early life immunization and demonstrate its ability to significantly improve the protective efficacy of an inactivated influenza virus vaccine in a neonatal mouse model. The GVI3000 adjuvant delivers a truncated, self-replicating viral RNA into dendritic cells in the draining lymph node. Intracellular RNA replication activates a strong innate immune response that significantly enhances adaptive antibody and cellular immune responses to codelivered antigens. A significant increase in protection results from a single immunization. Importantly, this adjuvant also primed a mucosal IgA response, which is likely to be critical for protection during many early life infections.

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IC31^®, a Two‐Component Novel Adjuvant Mixed with a Conjugate Vaccine Enhances Protective Immunity against Pneumococcal Disease in Neonatal Mice

Cited by 43 publications

References 37 publications

Novel Protein-Based Pneumococcal Vaccines Administered with the Th1-Promoting Adjuvant IC31 Induce Protective Immunity against Pneumococcal Disease in Neonatal Mice

Novel Protein-Based Pneumococcal Vaccines Administered with the Th1-Promoting Adjuvant IC31 Induce Protective Immunity against Pneumococcal Disease in Neonatal Mice

Concomitant Administration of Mycobacterium bovis BCG with the Meningococcal C Conjugate Vaccine to Neonatal Mice Enhances Antibody Response and Protective Efficacy

An Alphavirus-Based Adjuvant Enhances Serum and Mucosal Antibodies, T Cells, and Protective Immunity to Influenza Virus in Neonatal Mice

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IC31®, a Two‐Component Novel Adjuvant Mixed with a Conjugate Vaccine Enhances Protective Immunity against Pneumococcal Disease in Neonatal Mice

Cited by 43 publications

References 37 publications

Novel Protein-Based Pneumococcal Vaccines Administered with the Th1-Promoting Adjuvant IC31 Induce Protective Immunity against Pneumococcal Disease in Neonatal Mice

Novel Protein-Based Pneumococcal Vaccines Administered with the Th1-Promoting Adjuvant IC31 Induce Protective Immunity against Pneumococcal Disease in Neonatal Mice

Concomitant Administration of Mycobacterium bovis BCG with the Meningococcal C Conjugate Vaccine to Neonatal Mice Enhances Antibody Response and Protective Efficacy

An Alphavirus-Based Adjuvant Enhances Serum and Mucosal Antibodies, T Cells, and Protective Immunity to Influenza Virus in Neonatal Mice

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IC31^®, a Two‐Component Novel Adjuvant Mixed with a Conjugate Vaccine Enhances Protective Immunity against Pneumococcal Disease in Neonatal Mice