Safety and immunogenicity of a subtype C ALVAC-HIV (vCP2438) vaccine prime plus bivalent subtype C gp120 vaccine boost adjuvanted with MF59 or alum in healthy adults without HIV (HVTN 107): A phase 1/2a randomized trial.

BACKGROUND: Adjuvants are widely used to enhance and/or direct vaccine-induced immune responses yet rarely evaluated head-to-head. Our trial directly compared immune responses elicited by MF59 versus alum adjuvants in the RV144-like HIV vaccine regimen modified for the Southern African region. The RV144 trial of a recombinant canarypox vaccine vector expressing HIV env subtype B (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost adjuvanted with alum is the only trial to have shown modest HIV vaccine efficacy. Data generated after RV144 suggested that use of MF59 adjuvant might allow lower protein doses to be used while maintaining robust immune responses. We evaluated safety and immunogenicity of an HIV recombinant canarypox vaccine vector expressing HIV env subtype C (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost (gp120) adjuvanted with alum (ALVAC-HIV+gp120/alum) or MF59 (ALVAC-HIV+gp120/MF59) or unadjuvanted (ALVAC-HIV+gp120/no-adjuvant) and a regimen where ALVAC-HIV+gp120 adjuvanted with MF59 was used for the prime and boost (ALVAC-HIV+gp120/MF59 coadministration). METHODS AND FINDINGS: Between June 19, 2017 and June 14, 2018, 132 healthy adults without HIV in South Africa, Zimbabwe, and Mozambique were randomized to receive intramuscularly: (1) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/MF59 (months 3, 6, and 12), n = 36; (2) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/alum (months 3, 6, and 12), n = 36; (3) 4 doses of ALVAC-HIV+gp120/MF59 coadministered (months 0, 1, 6, and 12), n = 36; or (4) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/no adjuvant (months 3, 6, and 12), n = 24. Primary outcomes were safety and occurrence and mean fluorescence intensity (MFI) of vaccine-induced gp120-specific IgG and IgA binding antibodies at month 6.5. All vaccinations were safe and well-tolerated; increased alanine aminotransferase was the most frequent related adverse event, occurring in 2 (1.5%) participants (1 severe, 1 mild). At month 6.5, vaccine-specific gp120 IgG binding antibodies were detected in 100% of vaccinees for all 4 vaccine groups. No significant differences were seen in the occurrence and net MFI of vaccine-specific IgA responses between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/alum-prime-boost groups or between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/MF59 coadministration groups. Limitations were the relatively small sample size per group and lack of evaluation of higher gp120 doses. CONCLUSIONS: Although MF59 was expected to enhance immune responses, alum induced similar responses to MF59, suggesting that the choice between these adjuvants may not be critical for the ALVAC+gp120 regimen. TRIAL REGISTRATION: HVTN 107 was registered with the South African National Clinical Trials Registry (DOH-27-0715-4894) and ClinicalTrials.gov (NCT03284710).

A Randomised Clinical Trial of the Safety and Pharmacokinetics of VRC07-523LS Administered via Different Routes and Doses (HVTN 127/HPTN 087).

Background: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the only bnAb HIV prevention efficacy studies to date, the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. Greater efficacy is required before passively administered bnAbs become a viable option for HIV prevention; furthermore subcutaneous (SC) or intramuscular (IM) administration may be preferred. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. Methods: Participants were recruited between 02 February 2018 and 09 October 2018. 124 healthy participants without HIV were randomized to receive five VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), SC (T4: 2.5 mg/kg, T5: 5 mg/kg) or IM (T6: 2.5 mg/kg or P6: placebo) routes at four-month intervals. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA after the first dose through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum pharmacokinetics. Neutralization activity was measured in a TZM-bl assay and anti-drug antibodies (ADA) were assayed using a tiered bridging assay testing strategy. Results: Injections were well-tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusions were generally well-tolerated, with infusion reactions reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals) following the first administration were 29.0 µg/mL (25.2, 33.4), 58.5 µg/mL (49.4, 69.3), and 257.2 µg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 µg/mL (8.8, 13.3) and 22.8 µg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 µg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM concentrations immediately prior to the second administration were 3.4 µg/mL (2.5, 4.6), 6.5 µg/mL (5.6, 7.5), and 27.2 µg/mL (23.9, 31.0) with IV dosing; 0.97 µg/mL (0.65, 1.4) and 3.1 µg/mL (2.2, 4.3) with SC dosing, and 2.6 µg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titres, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titre ADA at a lone timepoint. VRC07-523LS has an estimated mean half-life of 42 days (95% CI: 40.5, 43.5), approximately twice as long as VRC01. Conclusions: VRC07-523LS was safe and well-tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens.

Protein dose-sparing effect of AS01B adjuvant in a randomized preventive HIV vaccine trial of ALVAC-HIV (vCP2438) and adjuvanted bivalent subtype C gp120.

BACKGROUND: HVTN 120 is a phase 1/2a randomized double-blind placebo-controlled HIV vaccine trial that evaluated the safety and immunogenicity of ALVAC-HIV (vCP2438) and MF59- or AS01B-adjuvanted bivalent subtype C gp120 Env protein at two dose levels in healthy HIV-uninfected adults. Trial registration URL https://clinicaltrials.gov/ct2/show/NCT03122223 and registration number NCT03122223. METHODS: Participants received ALVAC-HIV (vCP2438) alone or placebo at months 0 and 1. At months 3 and 6, participants received either placebo, ALVAC-HIV (vCP2438) with 200µg of bivalent subtype C gp120 adjuvanted with MF59 or AS01B, or ALVAC-HIV (vCP2438) with 40µg of bivalent subtype C gp120 adjuvanted with AS01B. Primary outcomes were safety and immune responses. RESULTS: We enrolled 160 participants, 55% females, 18-40 years old (median age 24 years) of whom 150 received vaccine and 10 placebo. Vaccines were generally safe and well tolerated. At months 6.5 and 12, CD4+ T-cell response rates and magnitudes were higher in the AS01B-adjuvanted groups than in the MF59-adjuvanted group. At month 12, HIV-specific Env-gp120 binding antibody response magnitudes in the 40µg gp120/AS01B group were higher than in either of the 200µg gp120 groups. CONCLUSIONS: The 40µg dose gp120/AS01B regimen elicited the highest CD4+ T-cell and binding antibody responses.

Post-COVID symptom profiles and duration in a global convalescent COVID-19 observational cohort: Correlations with demographics, medical history, acute COVID-19 severity and global region.

Background: Post-COVID conditions are characterised by persistent symptoms that negatively impact quality of life after SARS-CoV-2 diagnosis. While post-COVID risk factors and symptoms have been extensively described in localised regions, especially in the global north, post-COVID conditions remain poorly understood globally. The global, observational cohort study HVTN 405/HPTN 1901 characterises the convalescent course of SARS-CoV-2 infection among adults in North and South America and Africa. Methods: We categorised the cohort by infection severity (asymptomatic, symptomatic, no oxygen requirement (NOR), non-invasive oxygen requirement (NIOR), invasive oxygen requirement (IOR)). We applied a regression model to assess correlations of demographics, co-morbidities, disease severity, and concomitant medications with COVID-19 symptom persistence and duration across global regions. Results: We enrolled 759 participants from Botswana, Malawi, South Africa, Zambia, Zimbabwe, Peru, and the USA a median of 51 (interquartile range (IQR) = 35-66) days post-diagnosis, from May 2020 to March 2021. 53.8% were female, 69.8% were 18-55 years old (median (md) = 44 years old, IQR = 33-58). Comorbidities included obesity (42.8%), hypertension (24%), diabetes (14%), human immunodeficiency virus (HIV) infection (11.6%) and lung disease (7.5%). 76.2% were symptomatic (NOR = 47.4%; NIOR = 22.9%; IOR = 5.8%). Median COVID-19 duration among symptomatic participants was 20 days (IQR = 11-35); 43.4% reported symptoms after COVID-19 resolution, 33.6% reported symptoms ≥30 days, 9.9% reported symptoms ≥60 days. Symptom duration correlated with disease severity (P < 0.001, NIOR vs NOR; P = 0.003, IOR vs NOR), lung disease (P = 0.001), race (P < 0.05, non-Hispanic Black vs White), and global region (P < 0.001). Prolonged viral shedding correlated with persistent abdominal pain (odds ratio (OR) = 5.51, P < 0.05) and persistent diarrhoea (OR = 6.64, P < 0.01). Conclusions: Post-COVID duration varied with infection severity, race, lung disease, and region. Better understanding post-COVID conditions, including regionally-diverse symptom profiles, may improve clinical assessment and management globally. Registration: Clinicaltrials.gov (#NCT04403880).

Neutralizing antibody responses over time in demographically and clinically diverse individuals recovered from SARS-CoV-2 infection in the United States and Peru: A cohort study.

BACKGROUND: People infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) experience a wide range of clinical manifestations, from asymptomatic and mild illness to severe illness and death, influenced by age and a variety of comorbidities. Neutralizing antibodies (nAbs) are thought to be a primary immune defense against the virus. Large, diverse, well-characterized cohorts of convalescent individuals provide standardized values to benchmark nAb responses to past SARS-CoV-2 infection and define potentially protective levels of immunity. METHODS AND FINDINGS: This analysis comprises an observational cohort of 329 HIV-seronegative adults in the United States (n = 167) and Peru (n = 162) convalescing from SARS-CoV-2 infection from May through October 2020. The mean age was 48 years (range 18 to 86), 54% of the cohort overall was Hispanic, and 34% identified as White. nAb titers were measured in serum by SARS-CoV-2.D614G Spike-pseudotyped virus infection of 293T/ACE2 cells. Multiple linear regression was applied to define associations between nAb titers and demographic variables, disease severity and time from infection or disease onset, and comorbidities within and across US and Peruvian cohorts over time. nAb titers peaked 28 to 42 days post-diagnosis and were higher in participants with a history of severe Coronavirus Disease 2019 (COVID-19) (p < 0.001). Diabetes, age >55 years, male sex assigned at birth, and, in some cases, body mass index were also independently associated with higher nAb titers, whereas hypertension was independently associated with lower nAb titers. nAb titers did not differ by race, underlying pulmonary disease or smoking. Two months post-enrollment, nAb ID50 (ID80) titers declined 3.5 (2.8)-fold overall. Study limitations in this observational, convalescent cohort include survivorship bias and missing early viral loads and acute immune responses to correlate with the convalescent responses we observed. CONCLUSIONS: In summary, in our cohort, nAb titers after SARS-CoV-2 infection peaked approximately 1 month post-diagnosis and varied by age, sex assigned at birth, disease severity, and underlying comorbidities. Our data show great heterogeneity in nAb responses among people with recent COVID-19, highlighting the challenges of interpreting natural history studies and gauging responses to vaccines and therapeutics among people with recent infection. Our observations illuminate potential correlations of demographic and clinical characteristics with nAb responses, a key element for protection from COVID-19, thus informing development and implementation of preventative and therapeutic strategies globally. TRIAL REGISTRATION: ClinicalTrials.gov NCT04403880.

Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase.

BACKGROUND: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported. METHODS: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021. RESULTS: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified. CONCLUSIONS: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

AIDSVAX protein boost improves breadth and magnitude of vaccine-induced HIV-1 envelope-specific responses after a 7-year rest period.

BACKGROUND: Eliciting durable humoral immunity with sufficient breadth and magnitude is important for HIV-1 vaccine design. The HVTN 114 vaccine trial evaluated different boost regimens administered after a 7-year rest period in participants previously enrolled in HVTN 205, who received either three MVA/HIV62B (MMM) or two DNA and two MVA/HIV62B (DDMM) injections; both vaccines expressed multiple HIV-1 antigens in non-infectious virus-like-particles. The primary objective of HVTN 114 was to assess the impact of a heterologous gp120 protein AIDSVAX B/E boost on the magnitude, breadth and durability of vaccine-induced immune responses. METHODS: We enrolled 27 participants from HVTN 205 into five groups. Eight participants who previously received MMM were randomized and boosted with either MVA/HIV62B alone (T1; n = 4) or MVA/HIV62B and AIDSVAX B/E (T2; n = 4). Nineteen participants who received DDMM were randomized and boosted with MVA/HIV62B alone (T3; n = 6), MVA/HIV62B and AIDSVAX B/E (T4; n = 6), or AIDSVAX B/E alone (T5; n = 7). Boosts were at months 0 and 4. Participants were followed for safety and immunogenicity for 10 months and were pooled for analysis based on the regimen: MVA-only (T1 + T3), MVA + AIDSVAX (T2 + T4), and AIDSVAX-only (T5). RESULTS: All regimens were safe and well-tolerated. Prior to the boost vaccination, binding antibody and CD4+T-cell responses were observed 7 years after HVTN 205 vaccinations. Late boosting with AIDSVAX, with or without MVA, resulted in high binding antibody responses to gp120 and V1V2 epitopes, with increased magnitude and breadth compared to those observed in HVTN 205. Late boosting with MVA, with or without AIDSVAX, resulted in increased gp140 and gp41 antibody responses and higher CD4+T-cell responses to Env and Gag. CONCLUSIONS: Late boosting with AIDSVAX, alone or in combination with MVA, can broaden binding antibody responses and increase T-cell responses even years following the original MVA/HIV62B with or without DNA-priming vaccine.

Meta-analysis of HIV-1 vaccine elicited mucosal antibodies in humans.

We studied mucosal immune responses in six HIV-1 vaccine trials investigating different envelope (Env)-containing immunogens. Regimens were classified into four categories: DNA/vector, DNA/vector plus protein, protein alone, and vector alone. We measured HIV-1-specific IgG and IgA in secretions from cervical (n = 111) and rectal swabs (n = 154), saliva (n = 141), and seminal plasma (n = 124) and compared to corresponding blood levels. Protein-containing regimens had up to 100% response rates and the highest Env-specific IgG response rates. DNA/vector groups elicited mucosal Env-specific IgG response rates of up to 67% that varied across specimen types. Little to no mucosal IgA responses were observed. Overall, gp41- and gp140-specific antibodies dominated gp120 mucosal responses. In one trial, prior vaccination with a protein-containing immunogen maintained durability of cervical and rectal IgG for up to 17 years. Mucosal IgG responses were boosted after revaccination. These findings highlight a role for protein immunization in eliciting HIV-1-specific mucosal antibodies and the ability of HIV-1 vaccines to elicit durable HIV-1-specific mucosal IgG.

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.

BACKGROUND: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. METHODS: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. RESULTS: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. CONCLUSIONS: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

Intramuscular and Intradermal Electroporation of HIV-1 PENNVAX-GP® DNA Vaccine and IL-12 Is Safe, Tolerable, Acceptable in Healthy Adults.

Background: Several techniques are under investigation to improve the immunogenicity of HIV-1 DNA vaccine candidates. DNA vaccines are advantageous due to their ease of design, expression of multiple antigens, and safety. METHODS: The HVTN 098 trial assessed the PENNVAX®-GP DNA vaccine (encoding HIV env, gag, pol) administered with or without plasmid IL-12 at 0-, 1-, 3-, and 6-month timepoints via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, adult participants. We report on safety, tolerability, and acceptability. RESULTS: HVTN 098 enrolled 94 participants: 85 received PENNVAX®-GP and nine received placebo. Visual analog scale (VAS) pain scores immediately after each vaccination were lower in the ID/EP than in the IM/EP group (medians 4.1-4.6 vs. 6-6.5, p < 0.01). IM/EP participants reported greater pain and/or tenderness at the injection site. Most ID/EP participants had skin lesions such as scabs/eschars, scars, and pigmentation changes, which resolved within 6 months in 51% of participants (24/55). Eighty-two percent of IM/EP and 92% of ID/EP participant survey responses showed acceptable levels of discomfort. CONCLUSIONS: ID/EP and IM/EP are distinct experiences; however, HIV-1 DNA vaccination by either route was safe, tolerable and acceptable by most study participants.

Robust antibody and cellular responses induced by DNA-only vaccination for HIV.

BACKGROUNDHVTN 098, a randomized, double-blind, placebo-controlled trial, evaluated the safety, tolerability, and immunogenicity of PENNVAX-GP HIV DNA vaccine, administered with or without plasmid IL-12 (pIL-12), via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, HIV-uninfected adults. The study tested whether PENNVAX-GP delivered via ID/EP at one-fifth the dose could elicit equivalent immune responses to delivery via IM/EP and whether inclusion of pIL-12 provided additional benefit.METHODSParticipants received DNA encoding HIV-1 env/gag/pol in 3 groups: 1.6 mg ID (ID no IL-12 group, n = 20), 1.6 mg ID + 0.4 mg pIL-12 (ID + IL-12 group, n = 30), 8 mg IM + 1 mg pIL-12 (IM + IL-12 group, n = 30), or placebo (n = 9) via EP at 0, 1, 3, and 6 months. Results of cellular and humoral immunogenicity assessments are reported.RESULTSFollowing vaccination, the frequency of responders (response rate) to any HIV protein based on CD4+ T cells expressing IFN-γ or IL-2 was 96% for both the ID + IL-12 and IM + IL-12 groups; CD8+ T cell response rates were 64% and 44%, respectively. For ID delivery, the inclusion of pIL-12 increased CD4+ T cell response rate from 56% to 96%. The frequency of responders was similar (≥90%) for IgG binding antibody to gp140 consensus Env across all groups, but the magnitude was higher in the ID + IL-12 group compared with the IM + IL-12 group.CONCLUSIONPENNVAX-GP DNA induced robust cellular and humoral immune responses, demonstrating that immunogenicity of DNA vaccines can be enhanced by EP route and inclusion of pIL-12. ID/EP was dose sparing, inducing equivalent, or in some aspects superior, immune responses compared with IM/EP.TRIAL REGISTRATIONClinicalTrials.gov NCT02431767.FUNDINGThis work was supported by National Institute of Allergy and Infectious Diseases (NIAID), U.S. Public Health Service grants, an HIV Vaccine Design and Development Team contract, Integrated Preclinical/Clinical AIDS Vaccine Development Program, and an NIH award.

Assessment of tissue allograft safety monitoring with administrative healthcare databases: a pilot project using Medicare data.

Assess whether Medicare data are useful for monitoring tissue allograft safety and utilization. We used health care claims (billing) data from 2007 for 35 million fee-for-service Medicare beneficiaries, a predominantly elderly population. Using search terms for transplant-related procedures, we generated lists of ICD-9-CM and CPT(®) codes and assessed the frequency of selected allograft procedures. Step 1 used inpatient data and ICD-9-CM procedure codes. Step 2 added non-institutional provider (e.g., physician) claims, outpatient institutional claims, and CPT codes. We assembled preliminary lists of diagnosis codes for infections after selected allograft procedures. Many ICD-9-CM codes were ambiguous as to whether the procedure involved an allograft. Among 1.3 million persons with a procedure ascertained using the list of ICD-9-CM codes, only 1,886 claims clearly involved an allograft. CPT codes enabled better ascertainment of some allograft procedures (over 17,000 persons had corneal transplants and over 2,700 had allograft skin transplants). For spinal fusion procedures, CPT codes improved specificity for allografts; of nearly 100,000 patients with ICD-9-CM codes for spinal fusions, more than 34,000 had CPT codes indicating allograft use. Monitoring infrequent events (infections) after infrequent exposures (tissue allografts) requires large study populations. A strength of the large Medicare databases is the substantial number of certain allograft procedures. Limitations include lack of clinical detail and donor information. Medicare data can potentially augment passive reporting systems and may be useful for monitoring tissue allograft safety and utilization where codes clearly identify allograft use and coding algorithms can effectively screen for infections.

Chart-confirmed guillain-barre syndrome after 2009 H1N1 influenza vaccination among the Medicare population, 2009-2010.

Given the increased risk of Guillain-Barré Syndrome (GBS) found with the 1976 swine influenza vaccine, both active surveillance and end-of-season analyses on chart-confirmed cases were performed across multiple US vaccine safety monitoring systems, including the Medicare system, to evaluate the association of GBS after 2009 monovalent H1N1 influenza vaccination. Medically reviewed cases consisted of H1N1-vaccinated Medicare beneficiaries who were hospitalized for GBS. These cases were then classified by using Brighton Collaboration diagnostic criteria. Thirty-one persons had Brighton level 1, 2, or 3 GBS or Fisher Syndrome, with symptom onset 1-119 days after vaccination. Self-controlled risk interval analyses estimated GBS risk within the 6-week period immediately following H1N1 vaccination compared with a later control period, with additional adjustment for seasonality. Our results showed an elevated risk of GBS with 2009 monovalent H1N1 vaccination (incidence rate ratio = 2.41, 95% confidence interval: 1.14, 5.11; attributable risk = 2.84 per million doses administered, 95% confidence interval: 0.21, 5.48). This observed risk was slightly higher than that seen with previous seasonal influenza vaccines; however, additional results that used a stricter case definition (Brighton level 1 or 2) were not statistically significant, and our ability to account for preceding respiratory/gastrointestinal illness was limited. Furthermore, the observed risk was substantially lower than that seen with the 1976 swine influenza vaccine.

Characterizing vaccine-associated risks using cubic smoothing splines.

Estimating risks associated with the use of childhood vaccines is challenging. The authors propose a new approach for studying short-term vaccine-related risks. The method uses a cubic smoothing spline to flexibly estimate the daily risk of an event after vaccination. The predicted incidence rates from the spline regression are then compared with the expected rates under a log-linear trend that excludes the days surrounding vaccination. The 2 models are then used to estimate the excess cumulative incidence attributable to the vaccination during the 42-day period after vaccination. Confidence intervals are obtained using a model-based bootstrap procedure. The method is applied to a study of known effects (positive controls) and expected noneffects (negative controls) of the measles, mumps, and rubella and measles, mumps, rubella, and varicella vaccines among children who are 1 year of age. The splines revealed well-resolved spikes in fever, rash, and adenopathy diagnoses, with the maximum incidence occurring between 9 and 11 days after vaccination. For the negative control outcomes, the spline model yielded a predicted incidence more consistent with the modeled day-specific risks, although there was evidence of increased risk of diagnoses of congenital malformations after vaccination, possibly because of a "provider visit effect." The proposed approach may be useful for vaccine safety surveillance.

Prenatal smoking cessation and the risk of delivering preterm and small-for-gestational-age newborns.

OBJECTIVE: To examine the association between prenatal smoking cessation and delivery of a preterm or small-for-gestational-age (SGA) newborn in a large U.S. subpopulation using the revised (2003) birth certificate, which now assesses maternal smoking status by trimester. METHODS: We analyzed a cohort of U.S.-resident, singleton births in the 11 states that used the revised birth certificate in 2005 (n=915,441). Self-reported maternal smoking status was categorized as "never smoked," "quit in the first trimester," "quit in the second trimester," and "smoked throughout" pregnancy (referent). Multinomial logistic regression was used to estimate adjusted odds ratios (aORs) for three outcomes (preterm non-SGA, term SGA, or preterm SGA newborns) by maternal smoking status. Analyses stratified by maternal age were also conducted. RESULTS: Compared with women who smoked throughout pregnancy, first-trimester quitters reduced their odds of delivering a preterm non-SGA newborn by 31% (aOR 0.69, 95% confidence interval [CI] 0.65-0.74), a term SGA newborn by 55% (aOR 0.45, 95% CI 0.42-0.48), and a preterm SGA newborn by 53% (aOR 0.47, 95% CI 0.40-0.55), similar to nonsmokers. Second-trimester quitters also reduced their odds of delivering preterm non-SGA and term SGA newborns but to a lesser magnitude. When comparing first-trimester quitters with smokers in each age group, older mothers had generally lower odds of these outcomes than younger mothers. CONCLUSION: Pregnant smokers who quit in the first trimester lowered their risk of delivering preterm and SGA newborns to a level similar to that of pregnant nonsmokers, and this benefit appeared to increase with maternal age. These findings reinforce current clinical guidance to encourage smoking cessation among pregnant smokers and serve as an additional incentive to quit. LEVEL OF EVIDENCE: II.