Defining the interval for monitoring potential adverse events following immunization (AEFIs) after receipt of live viral vectored vaccines

Live viral vectors that express heterologous antigens of the target pathogen are being investigated in the development of novel vaccines against serious infectious agents like HIV and Ebola. As some live recombinant vectored vaccines may be replication-competent, a key challenge is defining the length of time for monitoring potential adverse events following immunization (AEFI) in clinical trials and epidemiologic studies. This time period must be chosen with care and based on considerations of pre-clinical and clinical trials data, biological plausibility and practical feasibility. The available options include: (1) adapting from the current relevant regulatory guidelines; (2) convening a panel of experts to review the evidence from a systematic literature search to narrow down a list of likely potential or known AEFI and establish the optimal risk window(s); and (3) conducting “near real-time“ prospective monitoring for unknown clustering's of AEFI in validated large linked vaccine safety databases using Rapid Cycle Analysis for pre-specified adverse events of special interest (AESI) and Treescan to identify previously unsuspected outcomes. The risk window established by any of these options could be used along with (4) establishing a registry of clinically validated pre-specified AESI to include in case-control studies. Depending on the infrastructure, human resources and databases available in different countries, the appropriate option or combination of options can be determined by regulatory agencies and investigators

Defining the interval for monitoring potential adverse events following immunization (AEFIs) after receipt of live viral vectored vaccines

Live viral vectors that express heterologous antigens of the target pathogen are being investigated in the development of novel vaccines against serious infectious agents like HIV and Ebola. As some live recombinant vectored vaccines may be replication-competent, a key challenge is defining the length of time for monitoring potential adverse events following immunization (AEFI) in clinical trials and epidemiologic studies. This time period must be chosen with care and based on considerations of pre-clinical and clinical trials data, biological plausibility and practical feasibility. The available options include: (1) adapting from the current relevant regulatory guidelines; (2) convening a panel of experts to review the evidence from a systematic literature search to narrow down a list of likely potential or known AEFI and establish the optimal risk window(s); and (3) conducting “near real-time“ prospective monitoring for unknown clustering's of AEFI in validated large linked vaccine safety databases using Rapid Cycle Analysis for pre-specified adverse events of special interest (AESI) and Treescan to identify previously unsuspected outcomes. The risk window established by any of these options could be used along with (4) establishing a registry of clinically validated pre-specified AESI to include in case-control studies. Depending on the infrastructure, human resources and databases available in different countries, the appropriate option or combination of options can be determined by regulatory agencies and investigators

PaxVax CVD 103-HgR single-dose live oral cholera vaccine

Introduction: Cholera remains a problem in developing countries and a risk for travelers. Hypochlorhydria, blood group O, cardiac and renal disease increase the risk of developing cholera gravis. Oral vaccines containing inactivated Vibrio cholerae and requiring two doses are available in some countries. No cholera vaccine had been available for U.S. travelers for decades until 2016 when CVD 103-HgR (VAXCHORA™), an oral live attenuated vaccine, was licensed by the U.S. FDA. Areas covered: Enduring protection following wild-type cholera provided the rationale to develop a single-dose live oral vaccine. CVD 103-HgR is well-tolerated and protects against cholera caused by V. cholerae O1 of either serotype (Inaba, Ogawa) and biotype (El Tor, Classical). Since 90% vaccine efficacy is evident 10 days post-ingestion of a single dose, CVD 103-HgR can rapidly protect travelers. Vibriocidal antibody seroconversion correlates with protection; >90% of U.S. adult (including elderly) vaccinees seroconvert. The U.S. Public Health Service’s Advisory Committee on Immunization Practices recommends CVD 103-HgR for U.S. travelers to areas of ongoing cholera transmission. Expert commentary: Next steps include evaluations in children, post-licensure safety and effectiveness monitoring, diminishing cold chain constraints, optimizing a ‘high-dose’ formulation for developing countries, and diminishing/eliminating the need for water to administer a dose

A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for the Novavax COVID-19 Vaccine (NVX-CoV2373), a recombinant spike protein vaccine with Matrix-M adjuvant to prevent disease caused by SARS-CoV-2 viruses

Novavax, a global vaccine company, began evaluating NVX-CoV2373 in human studies in May 2020 and the pivotal placebo-controlled phase 3 studies started in November 2020; five clinical studies provided adult and adolescent clinical data for over 31,000 participants who were administered NVX-CoV2373. This extensive data has demonstrated a well-tolerated response to NVX-CoV2373 and high vaccine efficacy against mild, moderate, or severe COVID-19 using a two-dose series (Dunkle et al., 2022) [1], (Heath et al., 2021) [2], (Keech et al., 2020) [3], (Mallory et al., 2022) [4]. The most common adverse events seen after administration with NVX-CoV2373 were injection site tenderness, injection site pain, fatigue, myalgia, headache, malaise, arthralgia, nausea, or vomiting. In addition, immunogenicity against variants of interest (VOI) and variants of concern (VOC) was established with high titers of ACE2 receptor-inhibiting and neutralizing antibodies in these studies (EMA, 2022) [5], (FDA, 2023) [6]. Further studies on correlates of protection determined that titers of anti-Spike IgG and neutralizing antibodies correlated with efficacy against symptomatic COVID-19 established in clinical trials (p < 0.001 for recombinant protein vaccine and p = 0.005 for mRNA vaccines for IgG levels) (Fong et al., 2022) [7]. Administration of a booster dose of the recombinant protein vaccine approximately 6 months following the primary two-dose series resulted in substantial increases in humoral antibodies against both the prototype strain and all evaluated variants, similar to or higher than the antibody levels observed in phase 3 studies that were associated with high vaccine efficacy (Dunkle et al., 2022) [1], (Mallory et al., 2022) [4]. These findings, together with the well tolerated safety profile, support use of the recombinant protein vaccine as primary series and booster regimens

Oral priming with replicating adenovirus serotype 4 followed by subunit H5N1 vaccine boost promotes antibody affinity maturation and expands H5N1 cross-clade neutralization.

A Phase I trial conducted in 2009-2010 demonstrated that oral vaccination with a replication competent Ad4-H5 (A/Vietnam) vector with dosages ranging from 107-1011 viral particles was well tolerated. HA-specific T-cell responses were efficiently induced, but very limited hemagglutination-inhibiting (HI) humoral responses were measured. However, a single boost of Ad4-H5-Vtn vaccinated individuals with a unadjuvanted licensed H5N1 (A/Vietnam) subunit vaccine resulted in superior HI titers compared with unprimed subjects. In the current study, the impact of Ad4-H5 priming on the quality of the polyclonal humoral immune response was evaluated using a real-time kinetics assay by surface plasmon resonance (SPR). Total binding of serum polyclonal antibodies from the Ad4-H5-Vtn primed groups against both homologous H5N1-A/Vietnam/1194/2004 (clade 1) and heterologous A/Indonesia-5/2005 (clade 2.1) HA1 head domain was significantly higher compared with sera from individuals that received subunit H5N1 vaccination alone. SPR measurements also demonstrated that the antigen-antibody complex dissociation rates (a surrogate for antibody affinity) of serum antibodies against the HA1 of H5N1-A/Vietnam were significantly higher in the Ad4-H5 primed groups compared with those from the unprimed group. Furthermore, strong correlations were observed between the antibody affinities for HA1 (but not HA2) and the virus neutralization titers against the homologous strain and a panel of heterologous clade 2 H5N1 strains. These findings support the concept of oral prime-boost vaccine approaches against pandemic influenza to elicit long-term memory B cells with high affinity capable of rapid response to variant pandemic viruses likely to emerge and adapt to human transmissions

Defining the Interval for Monitoring Potential Adverse Events Following Immunization (AEFIs) After Receipt of Live Viral Vectored Vaccines

Live viral vectors that express heterologous antigens of the target pathogen are being investigated in the development of novel vaccines against serious infectious agents like HIV and Ebola. As some live recombinant vectored vaccines may be replication-competent, a key challenge is defining the length of time for monitoring potential adverse events following immunization (AEFI) in clinical trials and epidemiologic studies. This time period must be chosen with care and based on considerations of pre-clinical and clinical trials data, biological plausibility and practical feasibility. The available options include: (1) adapting from the current relevant regulatory guidelines; (2) convening a panel of experts to review the evidence from a systematic literature search to narrow down a list of likely potential or known AEFI and establish the optimal risk window(s); and (3) conducting near real-time prospective monitoring for unknown clustering\u27s of AEFI in validated large linked vaccine safety databases using Rapid Cycle Analysis for pre-specified adverse events of special interest (AESI) and Treescan to identify previously unsuspected outcomes. The risk window established by any of these options could be used along with (4) establishing a registry of clinically validated pre-specified AESI to include in case-control studies. Depending on the infrastructure, human resources and databases available in different countries, the appropriate option or combination of options can be determined by regulatory agencies and investigators

Ad4-H5-Vtn priming enhances antibody affinity (slower off-rates) to H5N1-HA1 (but not HA2) following a single H5N1 subunit vaccine boost.

<p>(A-C) SPR analysis of post-H5N1 vaccinated human sera after the H5N1-A/Vietnam/1203/2004 subunit vaccine boost in three vaccine groups was performed with properly folded HA1 (A) or HA2 (B) from H5N1 A/Vietnam/1203/2004 strain, or rHA1 of the heterologous H5N1-A/Indonesia/5/2005 (Clade 2.1) strain (C). Off-rates of polyclonal serum antibodies before (open symbols) or 28 days (filled symbols) after a single H5N1 (A/Vietnam) booster vaccination from low dose Ad4-H5-Vtn primed (red circles), high dose Ad4-H5-Vtn primed (blue circles) or unprimed (green circles) individuals are shown from either 28 days after the third prime (P-P), and 28 days post boost with 90 μg HA/dose of the Sanofi Pasteur vaccine (P-V). Antibody off-rate constants that describe the fraction of antibody-antigen complexes decaying per second were determined directly from the serum sample interaction with rHA1 (1–320) protein or rHA2 (331–480) using SPR in the dissociation phase. Serum antibody off-rate constants were determined as described in Materials and Methods. Differences between groups (<i>p-values</i>) were examined for statistical significance by the multiple comparison adjustment using Bonferroni method. <i>p-values</i> of less than 0.05 were considered significant.</p

Binding of post-H5N1 vaccination polyclonal human serum to properly folded HA1 proteins from A/Vietnam/1203/2004 and A/Indonesia/05/2005.

<p>Steady-state equilibrium analysis of the total binding antibodies in the polyclonal human vaccine sera to properly folded functional H5N1-A/Vietnam/1203/2004 HA1-His₆ (panel A) or H5N1-A/Indonesia/05/2005-His₆ (Panel B) was measured by SPR. Each individual post-boost H5N1 serum sample, diluted ten-fold, was injected simultaneously onto HA1 immobilized on a sensor chip through the free amine group and onto a blank flow cell, free of peptide. Maximum resonance unit (Max RU) values for HA1 binding by serum antibodies obtained from multiple individuals from either low dose (10⁷ VP) Ad4-H5-Vtn primed (red circles), high dose Ad4-H5-Vtn (10¹¹VP) (blue circle), or unprimed (green circles) on day 0 (Pre), 28 days after the third prime (P-P), and 28 days post boost with 90 μg HA/dose of the Sanofi Pasteur (P-V). Differences between groups (p-values) were examined for statistical significance by the multiple comparison adjustment using Bonferroni method. A <i>p-value</i> less than 0.05 was considered to be significant. ‘ns’ represents non-significant (<i>p = >0.05</i>).</p

Serum antibody off-rates to H5-Viet-rHA1 (but not rHA2) following heterologous prime-boost strongly correlate with the <i>in-vitro</i> neutralizing capacity against the homologous H5 vaccine viruses.

<p>Antibody off-rate constants were determined directly from the serum sample interaction with H5N1 rHA1 or rHA2 proteins using SPR in the dissociation phase. SPR analysis of post-boost vaccination human sera from all 3 vaccine groups combined was performed with rHA1 (A) or rHA2 (B) of the H5N1-A/Vietnam/1203/2004 strain, or rHA1 of the heterologous H5N1-A/Indonesia/5/2005 (Clade 2.1) strain (C). Each symbol represents one individual. Serum samples on day 28 following single H5N1 booster vaccination with the subunit H5N1 vaccine (Sanofi Pasteur, 90 μg HA/dose) from the low-dose Ad4-H5-Vtn adjuvanted primed (red circles), high-dose Ad4-H5-Vtn primes (blue circles), or unprimed (green circles) are shown. Antibody affinity of post-H5N1 vaccinated human sera against HA1 (but not HA2) of H5N1-A/Vietnam/1203/2004 correlated with the homologous virus microneutralization titers (MN) against the A/Vietnam/1203/2004 (H5N1). Similarly, polyclonal antibody affinity of post-H5N1 vaccinated human sera against HA1 of the heterologous H5N1-A/Indonesia/5/2005 (Clade 2.1) strain correlated with the microneutralization titers (MN) against the A/Indonesia/5/2005 (H5N1) virus. Spearman correlations are reported for the calculation of correlations between off-rate and MN titers combined across all vaccine groups.</p

H5N1 prime-boost vaccine trial design.

<p>The vaccine study design representing the three groups that were used in the current study and the individual numbers (N) per group is indicated. For more details of the clinical study see Reference <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115476#pone.0115476.ref003" target="_blank">3</a>. Ad4-H5N1-Viet and MIV-H5N1-Viet refer to: Ad4-H5-Vtn is a recombinant, replication competent Ad4, encoding full-length haemagglutinin from influenza A H5N1 virus (A/Vietnam/1194/2004) given orally thrice either as 10⁷ virus particles (VP) or 10¹¹ virus particles per dose. MIV-H5N1-Viet is a formalin-inactivated, licensed inactivated H5N1 partially purified subunit vaccine (A/Vietnam, 90 μg HA/dose; Sanofi Pasteur).</p