Poor CD4+ T Cell Immunogenicity Limits Humoral Immunity to P. falciparum Transmission-Blocking Candidate Pfs25 in Humans

Plasmodium falciparum transmission-blocking vaccines (TBVs) targeting the Pfs25 antigen have shown promise in mice but the same efficacy has never been achieved in humans. We have previously published pre-clinical data related to a TBV candidate Pfs25-IMX313 encoded in viral vectors which was very promising and hence progressed to human clinical trials. The results from the clinical trial of this vaccine were very modest. Here we unravel why, contrary to mice, this vaccine has failed to induce robust antibody (Ab) titres in humans to elicit transmission-blocking activity. We examined Pfs25-specific B cell and T follicular helper (Tfh) cell responses in mice and humans after vaccination with Pfs25-IMX313 encoded by replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA) delivered in the heterologous prime-boost regimen via intramuscular route. We found that after vaccination, the Pfs25-IMX313 was immunologically suboptimal in humans compared to mice in terms of serum Ab production and antigen-specific B, CD4+ and Tfh cell responses. We identified that the key determinant for the poor anti-Pfs25 Ab formation in humans was the lack of CD4+ T cell recognition of Pfs25-IMX313 derived peptide epitopes. This is supported by correlations established between the ratio of proliferated antigen-specific CD4+/Tfh-like T cells, CXCL13 sera levels, and the corresponding numbers of circulating Pfs25-specific memory B cells, that consequently reflected on antigen-specific IgG sera levels. These correlations can inform the design of next-generation Pfs25-based vaccines for robust and durable blocking of malaria transmission.

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Antibody Avidity in Humoral Immune Responses in Bangladeshi Children and Adults following Administration of an Oral Killed Cholera Vaccine

Clinical and Vaccine Immunology ◽

10.1128/cvi.00341-13 ◽

2013 ◽

Vol 20 (10) ◽

pp. 1541-1548 ◽

Cited By ~ 6

Author(s):

Mohammad Murshid Alam ◽

Daniel T. Leung ◽

Marjahan Akhtar ◽

Mohammad Nazim ◽

Sarmin Akter ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

T Cell Responses ◽

Memory B Cell ◽

Antibody Avidity ◽

Memory T Cell ◽

Cell Responses ◽

Specific Memory ◽

Iga Antibodies ◽

Specific Igg

ABSTRACTAntibody avidity for antigens following disease or vaccination increases with affinity maturation and somatic hypermutation. In this study, we followed children and adults in Bangladesh for 1 year following oral cholera vaccination and measured the avidity of antibodies to the T cell-dependent antigen cholera toxin B subunit (CTB) and the T cell-independent antigen lipopolysaccharide (LPS) in comparison with responses in other immunological measurements. Children produced CTB-specific IgG and IgA antibodies of high avidity following vaccination, which persisted for several months; the magnitudes of responses were comparable to those seen in adult vaccinees. The avidity of LPS-specific IgG and IgA antibodies in vaccinees increased significantly shortly after the second dose of vaccine but waned rapidly to baseline levels thereafter. CTB-specific memory B cells were present for only a short time following vaccination, and we did not find significant memory B cell responses to LPS in any age group. For older children, there was a significant correlation between CTB-specific memory T cell responses after the second dose of vaccine and CTB-specific IgG antibody avidity indices over the subsequent year. These findings suggest that vaccination induces a longer-lasting increase in the avidity of antibodies to a T cell-dependent antigen than is measured by a memory B cell response to that antigen and that early memory T cell responses correlate well with the subsequent development of higher-avidity antibodies.

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SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best

Journal of Clinical Immunology ◽

10.1007/s10875-021-01133-0 ◽

2021 ◽

Author(s):

Ane Fernandez Salinas ◽

Eva Piano Mortari ◽

Sara Terreri ◽

Concetta Quintarelli ◽

Federica Pulvirenti ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Immune Responses ◽

Vaccine Dose ◽

Memory B Cells ◽

Cell Responses ◽

Specific Memory ◽

Immune Deficiencies ◽

Iga Antibody ◽

Specific Igg

Abstract Background Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. Methods Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. Results The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. Conclusion In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.

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A High Frequency of HIV-Specific Circulating Follicular Helper T Cells Is Associated with Preserved Memory B Cell Responses in HIV Controllers

mBio ◽

10.1128/mbio.00317-18 ◽

2018 ◽

Vol 9 (3) ◽

Cited By ~ 11

Author(s):

M. Claireaux ◽

M. Galperin ◽

D. Benati ◽

A. Nouël ◽

M. Mukhopadhyay ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Helper T Cells ◽

Memory B Cell ◽

Cell Responses ◽

Follicular Helper ◽

Specific Igg ◽

B Cell Responses ◽

Controller Group ◽

Hiv Controllers

ABSTRACT Follicular helper T cells (Tfh) play an essential role in the affinity maturation of the antibody response by providing help to B cells. To determine whether this CD4 + T cell subset may contribute to the spontaneous control of HIV infection, we analyzed the phenotype and function of circulating Tfh (cTfh) in patients from the ANRS CO21 CODEX cohort who naturally controlled HIV-1 replication to undetectable levels and compared them to treated patients with similarly low viral loads. HIV-specific cTfh (Tet + ), detected by Gag-major histocompatibility complex class II (MHC-II) tetramer labeling in the CD45RA − CXCR5 + CD4 + T cell population, proved more frequent in the controller group ( P = 0.002). The frequency of PD-1 expression in Tet + cTfh was increased in both groups (median, >75%) compared to total cTfh (<30%), but the intensity of PD-1 expression per cell remained higher in the treated patient group ( P = 0.02), pointing to the persistence of abnormal immune activation in treated patients. The function of cTfh, analyzed by the capacity to promote IgG secretion in cocultures with autologous memory B cells, did not show major differences between groups in terms of total IgG production but proved significantly more efficient in the controller group when measuring HIV-specific IgG production. The frequency of Tet + cTfh correlated with HIV-specific IgG production ( R = 0.71 for Gag-specific and R = 0.79 for Env-specific IgG, respectively). Taken together, our findings indicate that key cTfh-B cell interactions are preserved in controlled HIV infection, resulting in potent memory B cell responses that may play an underappreciated role in HIV control. IMPORTANCE The rare patients who spontaneously control HIV replication in the absence of therapy provide a unique model to identify determinants of an effective anti-HIV immune response. HIV controllers show signs of particularly efficient antiviral T cell responses, while their humoral response was until recently considered to play only a minor role in viral control. However, emerging evidence suggests that HIV controllers maintain a significant but “silent” antiviral memory B cell population that can be reactivated upon antigenic stimulation. We report that cTfh help likely contributes to the persistence of controller memory B cell responses, as the frequency of HIV-specific cTfh correlated with the induction of HIV-specific antibodies in functional assays. These findings suggest that T follicular help may contribute to HIV control and highlight the need for inducing such help in HIV vaccine strategies that aim at eliciting persistent B cell responses.

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Induction of Broad and Polyfunctional HIV-1-Specific T Cell Responses by the Multiepitopic Protein TMEP-B Vectored by MVA Virus

Vaccines ◽

10.3390/vaccines7030057 ◽

2019 ◽

Vol 7 (3) ◽

pp. 57

Author(s):

Beatriz Perdiguero ◽

Cristina Sánchez-Corzo ◽

Carlos Oscar S. Sorzano ◽

Pilar Mediavilla ◽

Lidia Saiz ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Immune Deficiency Syndrome ◽

Cd8 T Cell ◽

Deficiency Syndrome ◽

Aids Vaccine ◽

Cell Responses ◽

Follicular Helper ◽

Modified Vaccinia Virus Ankara ◽

Hiv 1

A human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) vaccine able to induce long-lasting immunity remains a major challenge. We previously designed a T cell multiepitopic immunogen including protective conserved epitopes from HIV-1 Gag, Pol and Nef proteins (TMEP-B), that induced potent HIV-1-specific CD8 T cells when vectored by DNA and combined with the vaccine candidate modified vaccinia virus Ankara (MVA)-B. Here, we described the vectorization of TMEP-B in MVA (MVA-TMEP) and evaluated the T cell immunogenicity profile elicited in mice when administered in homologous (MVA/MVA) or heterologous (DNA/MVA) prime/boost vector regimens or using homologous or heterologous inserts. The heterologous vector regimen was superior to the homologous protocol in inducing T cell responses. DNA-TMEP-primed animals boosted with MVA-TMEP or MVA-B exhibited the highest magnitudes of HIV-1-specific CD8, CD4 and T follicular helper (Tfh) cells, with MVA-TMEP significantly expanding Gag-specific CD8 T cell responses. In the homologous vector regimen, all groups exhibited similar HIV-1-specific CD8 and CD4 T cell responses, but both MVA-B/MVA-B and MVA-TMEP/MVA-TMEP combinations elicited higher Gag-Pol-Nef (GPN)-specific CD8 T cell responses compared to MVA-TMEP/MVA-B. Our results revealed an enhanced induction of HIV-1-specific T cell responses by TMEP-B when vectored in both DNA and MVA, and supported their use in combined prime/boost strategies for HIV-1 prevention and/or therapy.

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Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19

Nature Communications ◽

10.1038/s41467-021-21444-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Adam K. Wheatley ◽

Jennifer A. Juno ◽

Jing J. Wang ◽

Kevin J. Selva ◽

Arnold Reynaldi ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Vaccine Development ◽

Natural Infection ◽

Population Level ◽

Cell Dynamics ◽

Follicular Helper ◽

Cell Immunity ◽

Specific Igg ◽

Over Time

AbstractThe durability of infection-induced SARS-CoV-2 immunity has major implications for reinfection and vaccine development. Here, we show a comprehensive profile of antibody, B cell and T cell dynamics over time in a cohort of patients who have recovered from mild-moderate COVID-19. Binding and neutralising antibody responses, together with individual serum clonotypes, decay over the first 4 months post-infection. A similar decline in Spike-specific CD4+ and circulating T follicular helper frequencies occurs. By contrast, S-specific IgG+ memory B cells consistently accumulate over time, eventually comprising a substantial fraction of circulating the memory B cell pool. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent participants to 74 days, although there is probably additive protection from B cell and T cell immunity. This study indicates that SARS-CoV-2 immunity after infection might be transiently protective at a population level. Therefore, SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long-term protection.

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Immediate-Early Expression of a Recombinant Antigen by Modified Vaccinia Virus Ankara Breaks the Immunodominance of Strong Vector-Specific B8R Antigen in Acute and Memory CD8 T-Cell Responses

Journal of Virology ◽

10.1128/jvi.00604-10 ◽

2010 ◽

Vol 84 (17) ◽

pp. 8743-8752 ◽

Cited By ~ 33

Author(s):

Karen Baur ◽

Kay Brinkmann ◽

Marc Schweneker ◽

Juliane Pätzold ◽

Christine Meisinger-Henschel ◽

...

Keyword(s):

T Cell ◽

Vaccinia Virus ◽

T Cell Responses ◽

Cd8 T Cell ◽

Immediate Early ◽

Egfp Expression ◽

Cell Responses ◽

Modified Vaccinia Virus Ankara ◽

Memory Cd8 T Cell ◽

Early Late

ABSTRACT Efficient T-cell responses against recombinant antigens expressed by vaccinia virus vectors require expression of these antigens in the early phase of the virus replication cycle. The kinetics of recombinant gene expression in poxviruses are largely determined by the promoter chosen. We used the highly attenuated modified vaccinia virus Ankara (MVA) to determine the role of promoters in the induction of CD8 T-cell responses. We constructed MVA recombinants expressing either enhanced green fluorescent protein (EGFP) or chicken ovalbumin (OVA), each under the control of a hybrid early-late promoter (pHyb) containing five copies of a strong early element or the well-known early-late p7.5 or pS promoter for comparison. In primary or cultured cells, EGFP expression under the control of pHyb was detected within 30 min, as an immediate-early protein, and remained higher over the first 6 h of infection than p7.5- or pS-driven EGFP expression. Repeated immunizations of mice with recombinant MVA expressing OVA under the control of the pHyb promoter led to superior acute and memory CD8 T-cell responses compared to those to p7.5- and pS-driven OVA. Moreover, OVA expressed under the control of pHyb replaced the MVA-derived B8R protein as the immunodominant CD8 T-cell antigen after three or more immunizations. This is the first demonstration of an immediate-early neoantigen expressed by a poxviral vector resulting in superior induction of neoantigen-specific CD8 T-cell responses.

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Novel Recombinant Mycobacterium bovis BCG, Ovine Atadenovirus, and Modified Vaccinia Virus Ankara Vaccines Combine To Induce Robust Human Immunodeficiency Virus-Specific CD4 and CD8 T-Cell Responses in Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.02607-09 ◽

2010 ◽

Vol 84 (12) ◽

pp. 5898-5908 ◽

Cited By ~ 19

Author(s):

Maximillian Rosario ◽

Richard Hopkins ◽

John Fulkerson ◽

Nicola Borthwick ◽

Máire F. Quigley ◽

...

Keyword(s):

T Cell ◽

Vaccinia Virus ◽

Mycobacterium Bovis ◽

Ex Vivo ◽

Rhesus Macaques ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Modified Vaccinia Virus Ankara ◽

Hiv 1

ABSTRACT Mycobacterium bovis bacillus Calmette-Guérin (BCG), which elicits a degree of protective immunity against tuberculosis, is the most widely used vaccine in the world. Due to its persistence and immunogenicity, BCG has been proposed as a vector for vaccines against other infections, including HIV-1. BCG has a very good safety record, although it can cause disseminated disease in immunocompromised individuals. Here, we constructed a recombinant BCG vector expressing HIV-1 clade A-derived immunogen HIVA using the recently described safer and more immunogenic BCG strain AERAS-401 as the parental mycobacterium. Using routine ex vivo T-cell assays, BCG.HIVA401 as a stand-alone vaccine induced undetectable and weak CD8 T-cell responses in BALB/c mice and rhesus macaques, respectively. However, when BCG.HIVA401 was used as a priming component in heterologous vaccination regimens together with recombinant modified vaccinia virus Ankara-vectored MVA.HIVA and ovine atadenovirus-vectored OAdV.HIVA vaccines, robust HIV-1-specific T-cell responses were elicited. These high-frequency T-cell responses were broadly directed and capable of proliferation in response to recall antigen. Furthermore, multiple antigen-specific T-cell clonotypes were efficiently recruited into the memory pool. These desirable features are thought to be associated with good control of HIV-1 infection. In addition, strong and persistent T-cell responses specific for the BCG-derived purified protein derivative (PPD) antigen were induced. This work is the first demonstration of immunogenicity for two novel vaccine vectors and the corresponding candidate HIV-1 vaccines BCG.HIVA401 and OAdV.HIVA in nonhuman primates. These results strongly support their further exploration.

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