Study design
This human clinical study was designed and conducted in accordance with the provisions of the Declaration of Helsinki (1996) and the International Conference on Harmonisation Guidelines for Good Clinical Practice. The trial is registered at the EU Clinical Trial database (EudraCT number 2016-003678-42) and was approved by the Medical Research Ethics Committee United (MEC-U, NL60807.100.17-R17.039) in the Netherlands and the South Central - Hampshire B Research Ethics Committee (REC, 19/SC/0368) in the UK. Written informed consent was provided by participants and/or legal guardians at the start of the study, after the nature and possible consequences of the studies were explained. Clinical data of participants was recorded using OpenClinica, electronic case record form software that enables compliance with regulatory guidelines such as 21 CFR Part 11. The same online database system was used across the Dutch and UK sites. In the Netherlands, participants/parents/legal guardians were asked to keep their vaccination booklets at hand for the first visit. In case participants/parents/legal guardians did not have a vaccination booklet anymore, permission was asked to contact DVP (Vaccine Supply and Prevention Programs Service) to check their vaccination status according to NIP. In the UK, vaccination history was obtained either from the childs Red Book, or alternatively by means of the participant seeking confirmation from the GP recorded on a standard document.
The aim of this study was to identify early molecular and cellular correlates in peripheral blood that are associated with the humoral response that is mounted in response to Tdap-IPV vaccination in healthy adolescents. This study was conducted as part of a larger multi-center phase IV clinical study that evaluated immune responses to Tdap-IPV vaccination in participants from the United Kingdom, Finland, and the Netherlands7. Participants in the Dutch arm of the study were enrolled between October 2017 and March 2018. Participants were recruited by mail-outs in the Hoofddorp region, facilitated by the Municipal Administration, and the study was conducted by the Spaarne Academy (Spaarne Hospital, Hoofddorp, the Netherlands). Participants in the UK cohort were enrolled between April 2018 and January 2020 via mail out to eligible participants within postal areas. Participants in the NL or UK cohorts were included if they were in good health and had received all regular vaccines for their age group according to the Dutch or UK national immunization program (NIP), including an aP booster vaccination in preschool. Sex was not explicitly considered in the study design and all children between ages 11 and 15 years old were eligible for inclusion in the study. Male and female adolescents with either aP or wP vaccination priming backgrounds were included in the present study (NL cohort: N=14, 8 males and 6 females; UK cohort: N=12, 6 males and 6 females), TableS1. Assignment of aP or wP background in this study was basedon the participant date of birth and the available pertussis vaccine in the Netherlands at that time7. The number of participants included in the present study was informed on the basis of feasibility for carrying out a study for systems vaccinology. All participants received a dose of Tdap-IPV vaccine (BoostrixTM-IPV, GlaxoSmithKline (GSK), Wavre, Belgium) administered by intramuscular injection in the deltoid muscle of the upper arm at baseline (D0). The primary outcome was pertussis toxin-specific IgG antibody concentration at D28 post-vaccination. Secondary outcomes include but are not limited to IgG responses against the other Tdap vaccine antigens TT, Dt, Prn, FHA at D0, D28, and Y1, and PT at D0 and Y1. Exploratory outcomes relevant for this manuscript were measured at D0 and D1 post-vaccination, whole blood transcriptomic analysis, measurements of immune cell abundance and cytokine production by mass cytometry, and single-cell gene expression profiling of innate immune cells.
Whole blood was collected in tubes containing sodium heparin (Greiner vacuette in 4ml, 6ml, and 9ml volumes, catalog numbers 454030, 456028, 455051) to prevent coagulation. Complete blood counts were obtained using a Sysmex XN-450 hematology analyzer and sera were stored at 20oC until analysis. Whole blood was processed for single-cell RNA sequencing or mass cytometry analysis (detailed below). Whole blood was also collected directly in PAXgene Blood RNA Kit tubes (PreAnalytix) for transcriptome analysis and frozen at 80oC until processing.
Sera were analyzed for PT-, FHA-, Prn-, TT-, and Dt-specific IgG antibody concentrations using a fluorescent-bead-based multiplex immunoassay29. Antigens were covalently coupled to distinct color-coded activated carboxylated MicroPlex Microspheres (beads) (Luminex, Austin, Texas, USA) according to the manufacturers instructions. The following antigens were used for coupling: PT (GSK, Belgium), FHA (Sanofi, France), Prn (GSK, Belgium), diphtheria toxoid (Netherlands Vaccine Institute) and TT (T3194, Sigma-Aldrich, Saint Louis, Missouri, USA). After a wash step in PBS, 12.5106 carboxylated beads/mL were activated in PBS containing 2.5mg of 1-ethyl-3-(-3-dimethylaminopropyl)-carbodiimide hydrochloride (Thermo Fisher Scientific, Waltham, Massachusetts, USA) and 2.5mg of N-hydroxy-sulfosuccinimide (Thermo Fisher Scientific, Waltham, Massachusetts, USA). The antigens for coupling were diluted in PBS to a concentration of 10ug of PT, FHA or Prn, 100ug of Dt or 25ug of Tt per 12.5106 activated beads and incubated for 2h at room temperature in the dark under constant rotation. After 3 wash steps the antigen-coupled beads were stored in the dark in PBS containing 0.03% (wt/vol) sodium azide and 1% (wt/vol) bovine serum albumin at 4C until use.
Sera diluted 1/200 and 1/4000 in PBS containing 0.1% (vol/vol) Tween 20 and 3% (wt/vol) BSA were incubated with antigen-coupled beads in a 96-well filter plate for 45min at room temperature at 750rpm in the dark. Reference sera in a dilution series, quality control sera and blanks were included on each plate. The in-house reference standard for pertussis was calibrated against WHO 1st IS Pert 06/140 and serially diluted 4-fold over 6 wells (1/200 to 1/204800). The in-house reference standard for Dt and Tt was calibrated against WHO NIBSC DI-3 and TE-3 and serially diluted 4-fold over 8 wells (1/50 to 1/819200). Following incubation, wells were washed 3 times with PBS, incubated with R-phycoerythrin-labeled goat anti-human IgG antibody (Jackson Immunoresearch Laboratories, West-Grove, PA, USA, catalog number, 109-115-098, 1:200 dilution) for 30min and washed. Beads were included in PBS and median fluorescence intensity (MFI) was acquired on a Bio-Plex LX200. MFI was converted to IU/mL by interpolation from a 5-parameter logistic standard curve using Bioplex Manager 6.2 software (Bio-Rad Laboratories, Hercules, California, USA) and exported to Microsoft Excel.
Sera in the NL cohort were also analyzed for Polio.I, Polio.II, and Polio.III-specific IgG antibody concentrations using a fluorescent-bead-based multiplex immunoassay28. Type-specific capture monoclonal antibodies (MAb), respectively antipoliovirus type 1 clone 9B4 (HYB 295-17-02 ThermoFischer scientific, Waltham, MA USA), type 2 clone 24E2 (HYB 294-06-02 ThermoFischer scientific) and type 3 clone 4D5 (HYB 300-06-02 ThermoFischer scientific) were conjugated to three distinct activated carboxylated microspheres. Briefly, 800ul of carboxylated microspheres (12.5106 beads/ml; Bio-Rad Laboratories, Hercules, CA USA) were activated by adding 100l of 50mg/ml N-hydroxy-sulfosuccinimide (sulfo-NHS, ThermoFischer scientific) and 100l 50mg/ml 1-ethyl-3-(-3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC, ThermoFischer scientific) in PBS. The microspheres were activated at room temperature for 20min in the dark under constant rotation, washed once with 1ml PBS and resuspended in 1ml PBS containing 50g/ml of antipoliovirus monoclonal antibody. The beads were incubated for 2h at RT in the dark under constant rotation. Subsequently, the beads were washed three times with PBS and stored in the dark in PBS containing 0.05% (wt/vol) sodium azide and 1% (wt/vol) bovine serum albumin at 4C until use.
An in-house reference standard serum (RIVM MIA reference standard serum, Bilthoven, the Netherlands) was calibrated against the 3rd International Standard antiPoliovirus serum Types 1, 2 and 3 (NIBSC code: 82/585 assigned potency 11/32/3IU/ml) and used as the reference standard in the polio MIA assay. After calibration, the international standard was used as a control serum.
For quantification of Polio.I, Polio.II, and Polio.III antibodies in sample sera, reference standard serum, and control serum, sera were diluted and pre-incubated with monovalent IPV type 1, 2, 3 (National Vaccine Institute NVI/Bilthoven Biologicals, the Netherlands28) The reference standard (RIVM MIA reference standard serum) was diluted in 10 steps of 1.5-fold dilutions (1/181/692). Sample sera were diluted 1/2 and 1/25 and the control serum diluted 1/20 in dilution buffer (PBS containing 0.25% (v/v) Tween-20, 1% (w/v) BSA and 0.5M NaCl). Subsequently all dilutions were mixed 1:1 (v/v) with IPV in dilution buffer containing IPV type 1:56 DU/ml, IPV type 2:16 DU/ml and IPV type 3:80 DU/ml, ergo resulting in a final reference serum dilution of 1/361/1384, in serum dilutions of 1/4 and 1/50, in a control serum dilution of 1/40 and a IPV concentration of 0.7/0.2/1.0 DU/well (25ul) for IPV type 1, 2 and 3. After 2h incubation on a shaking platform (1000 RPM) at RT, 25ul of the samples, reference standard and controls dilutions were transferred to a pre-wetted 96-well Multiscreen HTS filter plate (Millipore Corporation, Billerica, MA) containing a 25ul per well mix of antipoliovirus MAb type 1, 2 and 3 conjugated microspheres (4000 beads/region/well) in dilution buffer. The plates were incubated for 1h at room temperature in the dark on a plate shaker at 600rpm. The beads were collected by filtration using a vacuum manifold and washed three times with 100ul PBS. A recombinant Human CD155/FC chimera (rhCD155/Fc 100gr, Sino Biological Inc. Beijing, China) was labeled with R-phycoerythrin (RPE) using the SiteClick RPE antibody labeling kit (ThermoFischer/life technologies) following manufacturers instructions and used for detection of IPV type 1, 2 and 3. To each well 50ul of a 1/2000 dilution of RPE conjugated CD155-Fc (1mg/ml) in PBS was added and the plate was incubated for 30min with continued shaking (600rpm). Plates were washed and beads were included in PBS and median fluorescence intensity (MFI) was acquired on a Bio-Plex LX200. MFI was converted to IU/mL by interpolation from a 5-parameter logistic standard curve using Bioplex Manager 6.2 software (Bio-Rad Laboratories, Hercules, California, USA) and exported to Microsoft Excel.
RNA extraction from whole blood, library preparation, sequencing, data processing, and differential gene expression analysis is described in the Supplementary Information.
Differential gene expression analysis of pre- (D0) and post-vaccination (D1) blood samples was performed with DESeq2 (v1.38.3), which takes a raw read count x sample matrix as input and includes library size normalization, estimation of dispersion, model fitting and gene filtering steps. We analyzed the effect of priming background (aP or wP vaccine) and sex on the vaccine response (D1 vs D0) with a model that included the background or sex variable, as well as its interaction with vaccination day and subject ID. A gene was considered differentially expressed if the FDR adjusted p-value was <0.05 and |log2 fold change|>0.5. As such, we analyzed gene expression with a final model that specifies vaccination day as the covariate of interest and controls for subject-level variations. The output from the DESeq2 pipeline includes a gene matrix with log2 fold change (D1/D0) and FDR-corrected p-values, which was used for downstream analysis.
Processing of whole blood samples for mass cytometry is described in the Supplementary Information.
FCS files were imported into Cytobank data analysis software (v6.1.2) and the arcsinh transform of marker expression values was calculated for downstream analysis. Major immune cell lineages were manually gated (Fig. S10A). For subpopulation analysis of APCs, manually gated monocytes, pDCs, and mDCs were exported per participant per timepoint, for a total of 24 FCS files (one pre- and one post-vaccination sample per participant for 12 participants). These files were imported into R (v3.6.1) for unsupervised clustering and subpopulation analysis according to a predefined workflow67. In total 285,780 APCs were identified across all 24 samples and were pooled for clustering, which was performed using the following markers: HLA-DR, CD69, CD31, CD86, CD16, CD123, CD33, CD14, CD1c, CD11c, CD62L, CD38, CD141, CD11b. Cluster markers were selected on the basis of their importance for describing heterogeneity and activation states among monocytes and dendritic cells. In total, 14 clusters were detected and manually annotated based on their phenotypic marker expression (Fig. S11A). Cluster abundance was similar across all samples (Fig. S11B). We derived a high-level stratification of cells for downstream analysis by manually merging clusters of APCs based on their similarity, which yielded eight subpopulations (phenotypic marker expression and the mapping of clusters to subpopulations is provided in Fig. S11C). The frequency of each cell type and APC subpopulation in our mass cytometry data was calculated as a fraction of CD45+ cells for each sample. These frequency values were multiplied by the total leukocyte counts (Fig. S10D) per ml of blood per sample to derive cell type (Fig. S10E) and APC subpopulation (Fig.4CE) abundance values. Expression values for analysis of intracellular cytokine responses were calculated as the mean signal intensity of each subpopulation for each sample. In order to identify co-expression of IL-6 and IFN-a in classical monocytes (Fig. S12), per donor, classical monocytes from D0 and D1 samples were pooled and the 95% quantile was calculated for each cytokine. Cells that were above the 95% quantile were classified as positive, and cells below this threshold were classified as negative. Thereafter, the frequency of single-positive or double-positive cells was calculated among all cells within a D1 or D0 sample.
Single-cell index sorting of immune cells, RNA extraction, library preparation, pre-processing of raw RNA sequencing data, filtering of low-quality cells, as well as pre-processing of single-cell FACS data is provided in the Supplementary Information.
We defined subpopulations of APCs by integrating FACS marker and single-cell gene expression to define populations using multi-omic factor analysis (MOFA68), which enables variance decomposition of the datasets and factors using the coefficient of determination (R2). The MOFA model was constructed using the single-cell FACS marker data and the top 30 principal components of the single-cell RNA sequencing data. We followed the developers directions for model selection and downstream analysis (https://biofam.github.io/MOFA2/tutorials.html). Both FACS and single-cell gene expression contributed substantially to the variation in the final model. Furthermore, several factors were identified with shared contributions from each dataset, thereby highlighting the utility of a joint analysis (Fig. S13D). To define subpopulations, we used the single-cell x MOFA factor graph for unsupervised clustering. Similar to the mass cytometry analysis, single-cell data was clustered using a two-step approach. The clusters that were identified are presented in Fig.6A, and their identity was verified by examining both single-cell surface marker and gene expression profiles. In total, we identified classical monocytes (cMo), intermediate monocytes (iMo), non-classical monocytes (ncMo), classical DC1 and DC2, as well as pDCs, which correspond to the same subpopulations previously defined in blood using integrated single-cell FACS and gene expression69.
We created pseudobulk RNA libraries by computationally pooling the gene expression of cells in a given subpopulation for a given pre- or post-vaccination sample. Cells from different single-cell RNA sequencing batches were also pooled. The total number of cells in each pseudobulk sample is shown in Fig. S6E, where each colored segment for each subpopulation represents the number of cells in a pseudobulk sample. The classical DC1 subpopulation was removed from downstream analysis since no sample had >10 cells. Next, raw gene counts of cells within a pseudobulk sample were summed together. We used the DESeq270 bulk RNAseq pipeline to perform differential gene expression analysis based on the developers directions (http://bioconductor.org/packages/devel/bioc/vignettes/DESeq2/inst/doc/DESeq2.html). We analyzed gene expression of each subpopulation separately with a model that specifies the number of days after vaccination as the covariate of interest and controls for subject-level variations. The output from the DESeq2 pipeline includes a gene matrix for each subpopulation with log2 fold change (D1/D0) and FDR-corrected p-values. These gene matrices were used for downstream analysis of differentially expressed genes (Fig.5C), GSEA (Fig.5D), and correlations with whole blood gene expression (Fig.5E).
GSEA of whole blood and single-cell RNA sequencing data, as well as the comparison with external Tdap vaccination data from in ref. 26. is provided in the Supplementary Information.
Details of the stimulation of peripheral blood mononuclear cells (PBMCs) from healthy donors with vaccines and mass cytometry analysis are provided in the Supplementary Information.
Antibody concentration values were log10-transformed to account for their skewed distribution. Antibody responses were calculated as log10-fold change (LFC) over baseline (D28 or Y1/D0). In order to account for the cross-correlation of LFC antibody responses with D0 antibody levels (Fig. S6), we calculated the adjusted LFC response as described previously in refs. 32,33. Briefly, for each antibody response, at each timepoint, and within each cohort, we fit a linear model with the LFC as the response and the log10 D0 antibody concentration as the predictor variable. Residuals from this model were extracted and summed with the intercept to obtain the adjLFC for each sample of every antibody response. Statistical comparisons of antibody concentrations, antibody responses, and phospho-signaling responses were calculated using a paired Wilcoxon test. Statistical parameters are reported directly in the figures and figure legends. Based on the similarity of antibody responses and transcriptional responses, participants were not separated based on sex or priming background in subsequent analyses (Mass cytometry and single-cell RNA sequencing analysis). Examination of the effects of Tdap-IPV vaccination with mass cytometry consisted of two parts: (i) differential expression (DE) of intracellular cytokines, and (ii) differential abundance (DA) analysis for each subpopulation of cells (TableS4). DE analysis was calculated using the mean signal intensity values for the indicated cytokines, for each subpopulation in each sample. DA analysis was performed on cell counts per unit of whole blood. For both DE and DA analyses, the effects of Tdap-IPV vaccination were determined using a linear mixed-effects model, fit with the lme4 (v1.133) R package71, with cell counts or mean signal intensity as the response, and vaccination day as the fixed effect. P values were generated using the lmerTest (v3.13) package72. We accounted for sample pairs (before and after vaccination) by introducing the subject ID as a random effect. P-values were extracted and corrected for multiple testing using Benjamini-Hochberg method73. Scatterplots displaying the correlation of LFC values with D0 antibody levels (Fig. S6, Fig. S17C) present Spearman correlation coefficient and associated p.value with linear regression trendline. Other statistical analyses (differential gene expression, GSEA) are reported in their respective section of the methods.
Further information on research design is available in theNature Portfolio Reporting Summary linked to this article.
New Centers for Disease Control and Prevention datais showing that newly released RSV vaccines are highly effective at keeping infants from becoming hospitalized.
The CDC says nirsevimab was 90% effective at preventing RSV-associated hospitalization in infants during their first RSV season. Nirsevimab wasapproved for babies and toddlers in July 2023.
The real-world usage of nirsevimab so far has outperformed data from clinical trials. Prior to its release, officials said nirsevimab reduced the risk of hospitalizations related to RSV among infants by 70%-75%.
"The current RSV season is the first time nirsevimab was available to protect infants from severe RSV, so the data released today are the first United States estimates of nirsevimab effectiveness in protecting infants against RSV-related hospitalization in their first season of potential exposure to the virus," the CDC said.
The study looked at 699 infants from October 2023 through February 2024. CDC officials did caution that its overall effectiveness may be lower once a full RSV season is complete. Generally, RSV activity declines in late March.
According to the CDC, RSV causes 58,000 hospitalizations annually among children under age 5.
SEE MORE: CDC: 128 pregnant people and 25 infants received the wrong RSV shot
The CDC said those most at risk for RSV include premature infants; very young infants, especially those 6 months and younger; and children younger than 2 years old with chronic lung disease or congenital heart disease.
Adults and older children who are healthy tend to have mild cases if infected. Early symptoms tend to include a runny nose, a decrease in appetite, and cough. Those symptoms can worsen, causing inflammation of the small airways in the lung.
The vaccine is recommended for all infants younger than 8 months born during or entering their first RSV season, if their mother did not get a maternal RSV vaccine. Another option is for pregnant people to get vaccinated during weeks 32 through 36 of their pregnancy if that period falls between September and January.
Trending stories at Scrippsnews.com
A line of the flu virus has been effectively wiped out, ironically thanks to COVID-19.
The Yamagata lineage is one of two varieties of Influenza B, which along with Influenza A subtypes, causes seasonal flu.
But no evidence of the Yamagata lineage has been detected globally since the outbreak of SARS-CoV-2 the virus that causes COVID-19 and the United States Food and Drug Administration has agreed with recommendations from the World Health Organization that it no longer be included in seasonal flu vaccines.
Yamagata was already in decline pre-pandemic, but none of its strains have been isolated since March 2020. Its believed containment measures introduced to prevent the spread of COVID-19 such as face masking and physical isolation may have helped to drive Yamagata to undetectable levels.
Last year, the WHO recommended only one Yamagata lineage be included in quadrivalent southern hemisphere seasonal flu vaccines. Its recent update for the 2024-25 northern hemisphere flu season said the inclusion of Yamagata-like viruses in trivalent jabs was no longer warranted.
Now, a meeting by the FDAs Vaccines and Related Biological Products Advisory Committee on Tuesday (local time) has ratified that recommendation. In a statement, the FDA said:
In the interest of public health, FDA strongly recommended to influenza vaccine manufacturers the removal of the B/Yamagata lineage virus from seasonal influenza vaccines in the U.S. for the 2024-2025 influenza season. FDA and the manufacturers have been working together so that the move from quadrivalent to trivalent seasonal influenza vaccines occurs for the upcoming influenza season.
The United States next batch of flu vaccines will include components of two Influenza A viruses and one Victoria lineage Influenza B virus.
Before the WHO and FDA announced their new directions, the August meeting of Australias Advisory Committee on Vaccines discussed the potential for removing the Yamagata lineage from future inoculations.
Robert Booy, an infectious diseases paediatrician at The Childrens Hospital at Westmead, tells Cosmos Yamagata was highly unlikely to return, but that its disappearance merely emphasises the competition between respiratory viruses in the environment.
The high likelihood is that Yamagata is gone, Booy says.
The four years of non-appearance has only year-on-year reinforced the understanding that there are a lot of other viruses out there competing for the biological niche in humans and this one has lost its way.
While he agrees with the decision by the WHO, FDA, and likely Australias TGA, to adopt a three-pronged flu vaccine for the future, he says there could be an opportunity to stick with a four-antigen jab that gives greater protection against the most potent A subtypes.
Influenza H3N2, which first appeared more than 50 years ago from the Hong Kong pandemic in 1962, is the most predominant cause of influenza and it continues to mutate and evolve and change so that our vaccines, even though theyre decided upon in the 6-12 months before theyre introduced, still only provide 50-70% protection, Booy says.
Some people therefore think that if we go for two different variants of H3, we could prevent the most damaging and most virulent cause of influenza each winter.
A German man deliberately got 213 COVID-19 vaccine shots in less than a year, becoming a walking experiment for what happens to the immune system when it is vaccinated repeatedly against the same pathogen.
The 62-year-old man from Magdeburg is not named in the correspondence in compliance with German privacy rules. Of the shots, 134 were confirmed by a prosecutor and through vaccination center documentation; the rest were self-reported.
According to his immunization history, the man got his first COVID vaccine in June 2021, then went on to get 16 more that year.
He ramped up his efforts in 2022, getting 48 shots in January and 34 in February.
Around that time, German Red Cross staff members in Dresden became suspicious and issued a warning to other vaccination centers, encouraging them to call the police if they saw the man, CNN affiliate RTL reported.
In March 2022, he was detained in a vaccination center in Eilenburg by police who suspected him of selling vaccination cards to third parties, according to RTL. The public prosecutor in Magdeburg opened an investigation but did not end up filing criminal charges, according to the study.
The researchers read about the man in the news and reached out to him in May 2022. He agreed to provide medical information, blood and saliva samples. By that point, he was 213 shots in; he later got four more, against the researchers medical advice, said Kilian Schober, senior author of the new study and a researcher at the Friedrich-Alexander University Erlangen-Nrnberg
This is a really unusual case of someone receiving that many COVID vaccines, clearly not following any type of guidelines, said Dr. Emily Happy Miller, an assistant professor of medicine and of microbiology and immunology at Albert Einstein College of Medicine who did not participate in the research.
The man did not report any vaccine-related side effects and has not had a COVID infection to date, as evidenced by repeated antigen and PCR testing between May 2022 and November 2023. The researchers caution that its not clear that his COVID status is directly because of his hypervaccination regimen.
Perhaps he didnt get COVID because he was well-protected in the first three doses of the vaccine, Miller said. We also dont know anything about his behaviors.
Schober said it is important to remember that this is an individual case study, and the results are not generalizable.
The researchers also say they do not endorse hypervaccination as a strategy to enhance immunity.
The benefit is not much bigger if you get vaccinated three times or 200 times, Schober said.
The researchers analyzed his blood chemistries, which showed no abnormalities linked to his hypervaccination. They also looked at various markers to evaluate how his adaptive immune system was functioning, according to the study.
In total, the man got eight vaccine formulations, including mRNA vaccines from Pfizer/BioNTech and Moderna, a vector-based vaccine from Johnson & Johnson and a recombinant-protein vaccine from Sanofi. He got them in both arms.
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The world needs an HIV vaccine if it ever hopes to beat a virus that still infects over 1 million people a year and contributes to hundreds of thousands of deaths.
Despite 20 years of failures in major HIV vaccine trials four this decade alone researchers say recent scientific advances have likely, hopefully, put them on the right track to develop a highly effective vaccine against the insidious virus.
But probably not until the 2030s.
An effective vaccine is really the only way to provide long-term immunity against HIV, and thats what we need, Dr. Julie McElrath, the director of the vaccine and infectious disease division at the Fred Hutchinson Cancer Center in Seattle, said Monday at the Conference on Retroviruses and Opportunistic Infections in Denver.
All current HIV vaccine action is in the laboratory, animal studies or very early human trials.
Researchers at the retrovirus conference presented favorable results from two HIV vaccine studies. One found that a modification to the simian version of HIV spurred production of what are known as broadly neutralizing antibodies against the virus in monkeys. Another showedpromise in the effort to coax the immune systems B cells to make the powerful antibodies in humans.
These trials illustrate as a proof of concept that we can train the immune system. But we need to further optimize it and test it in clinical trials, Karlijn van der Straten, a Ph.D. student at the Academic Medical Center at Amsterdam University, who presented the human study, said at a news conference Monday.
Still, the scrappy scientists in this field face a towering challenge. HIV is perhaps the most complex pathogen ever known.
The whole field has learned from the past, said William Schief, who leads Modernas HIV vaccine efforts. Weve learned strategies that dont work.
The cost has already been immense. Nearly $17 billion was spent worldwide on HIV -vaccine research from 2000 to 2021. Nearly $1 billion more is spent annually, according to the Joint United Nations Program on HIV/AIDS and the nonprofit HIV group AVAC.
Maintaining the funding for HIV vaccines right now is really important, said Dr. Nina Russell, who directs HIV research at the Bill & Melinda Gates Foundation. She pointed to the fields own progress and the excitement and to how HIV vaccine science and scientists continue to drive innovation and science that benefits other infectious diseases and global health in general.
Case in point: Covid. Thanks to HIV research, the mRNA vaccine technology was already available in 2020 to speed a coronavirus vaccine to market.
In strong contrast to Covid, the HIV vaccine endeavor has spanned four decades. Only one of the nine HIV vaccine trials have shown efficacy: a trial conducted in Thailand and published in 2009 that reported a modest 31% reduction in HIV risk.
HIV vaccine researchers subsequently spent years seeking to retool and improve that vaccine strategy, leading to a series of trials that launched in the late 2010s only to fail.
Researchers have concluded those latest trials were doomed because, aside from prompting an anti-HIV response based in immune cells, they only drove the immune system to produce what are known as non-neutralizing antibodies. Those weapons just werent strong enough for such a fearsome foe.
Preventing HIV through vaccination remains a daunting challenge because the immune system doesnt naturally mount an effective defense against the virus, as it does with so many other vaccine-preventable infections, including Covid. An HIV vaccine must coax from the body a supercharged immune response with no natural equivalent.
That path to victory is based on a crucial caveat: A small proportion of people with HIV do produce what are known as broadly neutralizing antibodies against the virus. They attack HIV in multiple ways and can neutralize a swath of variants of the virus.
Those antibodies dont do much apparent good for people who develop them naturally, because they typically dont arise until years into infection. HIV establishes a permanent reservoir in the body within about a week after infection, one that their immune response cant eliminate. So HIV-positive people with such antibodies still require antiretroviral treatment to remain healthy.
Researchers believe that broadly neutralizing antibodies could prevent HIV from ever seeding an infection, provided the defense was ready in advance of exposure. A pair of major efficacy trials, published in 2021, demonstrated that infusions of cloned versions of one such antibody did, indeed, protect people who were exposed to certain HIV strains that are susceptible to that antibody.
However, globally, those particular strains of the virus comprise only a small subset of all circulating HIV. That means researchers cant simply prompt a vaccine to produce that one antibody and expect it to be effective. Importantly, from this study they got a sense of what antibody level would be required to prevent infection.
Its a high benchmark, but at least investigators now have a clearer sense of the challenge before them.
Also frustrating the HIV vaccine quest is that the virus mutates like mad. Whatever spot on the surface of the virus that antibodies target might be prone to change through mutation, thus allowing the virus to evade their attack. Consequently, researchers search for targets on the virus surface that arent highly subject to mutation.
Experts also believe warding off the mutation threat will require targeting multiple sites on the virus. So researchers are seeking to develop a portfolio of immune system prompts that would spur production of an array of broadly neutralizing antibodies.
Prompting the development of such antibodies requires a complex, step-by step process of coaxing the infection-fighting B cells, getting them to multiply and then guiding their maturation into potent broadly neutralizing antibody-producing factories.
Dr. Carl Dieffenbach, the head of the AIDS division at the National Institute of Allergy and Infectious Diseases, said numerous recent technological advances including mRNA, better animal models of HIV infection and high-tech imaging technology have improved researchers precision in designing, and speed in producing, new proteins to spur anti-HIV immune responses.
Global collaboration among major players is also flourishing, researchers said. There are several early-stage human clinical trials of HIV-vaccine components underway.
Three mRNA-based early human trials of such components have been launched since 2022. Among them, they have been led or otherwise funded by the global vaccine research nonprofit group IAVI, Fred Hutch, Moderna, Scripps Research, the Gates Foundation, the National Institutes of Health, the U.S. Agency for International Development, and university teams. More such trials are in the works.
On Friday, Science magazine reported concerning recent findings that among the three mRNA trials, a substantial proportion of participants 7% to 18%, IAVI said in a statement experienced skin-related symptoms following injections, including hives, itching and welts.
IAVI said in its statement that it and partners are investigating the HIV trials skin-related outcomes, most of which were mild or moderate and managed with simple allergy medications.
Researchers have shown success in one of those mRNA trials in executing a particular step in the B-cell cultivation process.
That vaccine component also generated helper CD4 cells primed to combat HIV. The immune cells are expected to operate like an orchestra conductor for the immune system, coordinating a response by sending instructions to B cells and scaling up other facets of an assault on HIV.
A complementary strategy under investigation seeks to promote the development of killer CD8 cells that might be primed to kill off any immune cells that the antibodies failed to save from infection.
Crucially, investigators believe they are now much better able to discern top vaccine component candidates from the duds. They plan to spend the coming years developing such components so that when they do assemble the most promising among them into a multi-pronged vaccine, they can be much more confident of ultimate success in a trial.
An HIV vaccine could end HIV, McElrath said at the Denver conference. So I say, Lets just get on with it.
Dr. Mark Feinberg, president and CEO of IAVI, suggested that the first trial to test effectiveness of the vaccine might not launch until 2030 or later.
Even so, he was bullish.
The field of HIV vaccine development is in a better place now than its ever been, he said.
Benjamin Ryan is independent journalist specializing in science and LGBTQ coverage. He contributes to NBC News, The New York Times, The Guardianand Thomson Reuters Foundation and has also written for The Washington Post, The Nation, The Atlantic and New York.
March 8, 2024 On March 5, 2024, the FDAs Vaccines and Related Biological Products Advisory Committee (VRBPAC) met to discuss and make recommendations on the vaccine viruses for U.S. flu vaccines for the 2024-2025 flu season. The Committee recommended that all 2024-2025 U.S. flu vaccines be three-component (trivalent) vaccines and include an influenza A(H1N1), an A(H3N2) and a B/Victoria-lineage vaccine virus. Because influenza B/Yamagata viruses, which are included in current four-component (quadrivalent) flu vaccines, are no longer actively circulating, their inclusion in flu vaccines is no longer warranted.
Flu places a substantial health burden on the United States each year, sickening millions, hospitalizing hundreds of thousands and killing thousands to tens of thousands. Flu vaccines have been recommended in the United States for more than 50 years and have been shown to reduce the risk of flu and its potentially serious complications in people who get vaccinated. CDC recommends annual flu vaccination for everyone 6 months and older with rare exception.
The composition of U.S. flu vaccines is reviewed annually, and new flu vaccines are manufactured each year. From the 1958-1959 through 1977-1978 flu seasons, the number of vaccine viruses included in U.S. flu vaccines varied. From the 1978-1979 through 2012-2013 seasons, U.S. flu vaccines were trivalent. During those 35 seasons, flu vaccines included three vaccine viruses: an influenza A(H1N1), an A(H3N2), and a B-lineage vaccine virus (either from the B/Yamagata or B/Victoria lineage). Quadrivalent flu vaccines became available in the United States during the 2013-2014 flu season. These vaccines contained a fourth component-a second influenza B virus-in order to protect against both lineages of influenza B viruses. Quadrivalent flu vaccines were available in the United States from 2013-2014 to the current flu season (2023-2024). However, influenza B/Yamagata viruses have not been detected to be actively circulating in global surveillance after March 2020, and therefore, their inclusion in flu vaccines is no longer warranted.
According to an FDA statement: "FDA has been engaging and interacting with manufacturers of FDA-approved seasonal flu vaccines and providing scientific and regulatory advice to them to facilitate the timely availability of approved safe and effective trivalent seasonal flu vaccines for the 2024-2025 U.S. flu season. FDA anticipates that there will be an adequate and diverse supply of approved trivalent seasonal flu vaccines for the United States in the coming season."
Each year CDC publishes recommendations for the use of flu vaccines in the United States based on input from the Advisory Committee on Immunization Practices. The annual recommendations for the 2024-2025 flu vaccine are expected to publish in August 2024.
Kate O'Brien, Director of the Department of Immunization, Vaccines and Biologicals at WHO
In the coming months, the global immunization communitys attention will be immersed in two pivotal events which will underscore the importance of vaccination in safeguarding public health and well-being.
Kicking off the agenda is the Meeting of the Strategic Advisory Group of Experts (SAGE) on Immunization, slated for March 11-14. This gathering promises a comprehensive assessment of the Big Catch-Up initiative's progress, alongside an in-depth review of its monitoring, evaluation, and learning (MEL) strategy. SAGE members will provide feedback on fortifying the initiative's long-term impact and resilience. Moreover, they will delve into the progress being made on key elements of the Immunization Agenda 2030 strategy, issuing key recommendations on the polio, hepatitis E, and Mpox vaccines.
Following closely on the heels of SAGE, in Paris on April 26, the first WHO high-level meeting to defeat meningitis will sound a clarion call to action. This global gathering aims to galvanize commitments towards realizing the objectives detailed in the WHO Global Road Map to defeat meningitis by 2030. Meningitis continues to pose a significant threat to public health, with staggering global statistics of 236,000 deaths and 2.51 million incident cases recorded in 2019 alone.
Notably, the Paris high-level meeting synchronizes with the lead-up to the Olympic and Paralympic Games, which will see several athletes affected by meningitis competing. This opportunity is poised to elevate visibility for the Global Road Map's pivotal focus on bolstering care and support for affected individuals. Progress in the fight against meningitis is now more than just plans, with recent advancements such as the WHO's endorsement of a novel meningococcal conjugate vaccine tailored for the countries of the African meningitis belt, grappling with seasonal epidemics. The Men5CV vaccine holds immense promise, heralding a more impactful and cost-effective intervention for countries in the meningitis belt. Coupled with the Gavi Board's green light for expanding meningococcal programs to include Men5CV, the momentum towards defeating meningitis gains traction.
In a landmark moment in the fight against cervical cancer, governments, donors, multilateral institutions, and partners have collectively pledged nearly US$600 million in new funding towards the ambitious goal of eliminating cervical cancer. This unprecedented commitment, announced at the inaugural Global Cervical Cancer Elimination Forum this week in Cartagena de Indias, Colombia, marks a significant step towards eradicating this preventable disease on a global scale. With a focus on expanding HPV vaccination and strengthening screening, the goal is to eliminate this preventable disease that particularly impacts women in low and middle-income countries.
The Measles and Rubella Partnership convened in Washington, D.C., marking its first in-person meeting since 2019 and underscoring a pivotal moment in the global fight against these preventable diseases. Representatives from around the world gathered to strategize on key priorities, which include advancing the development of measles-rubella microarray patches and refining gap-filling campaigns to ensure targeted and effective interventions, especially for vulnerable populations. Additionally, discussions centered on leveraging improvements in measles programs to bolster primary healthcare initiatives, aiming to strengthen healthcare systems on a global scale. Through collaboration and knowledge-sharing, stakeholders aimed to overcome challenges and drive progress towards the shared goal of eradicating measles and rubella, shaping the future of public health efforts worldwide.
Amidst these advances, updated data from 2023 shed light on the escalating threat of measles outbreaks in Europe and beyond. Alarming spikes in cases underscore the urgent need for a concerted, robust response to safeguard vulnerable populations. The disproportionate toll on children below 5 years of age is a clear secondary impact of the COVID-19 pandemic. WHO and partners have warned throughout the pandemic of the eventuality that one crisis would spawn another, and now communities and countries are living those warning. Many countries are taking action to fill measles immunity gaps, yet predictions are that nearly half of countries remain at high or very high risk of imminent outbreaks underscoring the gravity of the situation and imperative to act now.
This year, 2024 is a pivotal juncture for the recovery of the immunization programme. It is the moment to fortify surveillance activities which are crucial for a well operating immunization programme, ramp up routine immunization service capacity and access, and execute targeted catch-up initiatives to fill the large immunity gaps that have grown to include older children.
The wider implementation of malaria vaccines across Africa is well underway. Earlier this year, Cameroon and Burkina Faso launched the first malaria vaccine, RTS,S/AS01 (RTS,S), as part of their routine immunization programmes, according to national malaria control plans, and malaria vaccination programmes are expanding in Ghana, Kenya and Malawi. More than 30 countries are expected to apply for Gavi support to deploy malaria vaccine. I recommend a recent article by WHO authors and experts in The Lancet "Malaria vaccines for children: and now there are two", which highlights the recently published results of the R21 vaccine phase 3 trial, and comments on the public health potential of two WHO-recommended and prequalified malaria vaccines.
Wide implementation of the malaria vaccines is expected to save tens of thousands of lives each year. Malaria vaccines are a breakthrough in the fight against malaria and early childhood deaths.
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New data released today inCDCsMMWRshow thatnirsevimab, a long-acting monoclonal antibody product,was highly effective in protecting infants from hospitalizations associated with respiratory syncytial virus (RSV).RSV is the leading cause of hospitalization among infants in the United States, and this finding supports CDCs recommendation to protectinfantsin their first RSV seasonby giving the infantnirsevimab if the mother did not receive the maternal RSV vaccine during pregnancy.
The current RSV season is the first time nirsevimab was available to protect infants from severe RSV, so the data released todayare the first United States estimatesofnirsevimabeffectiveness inprotectinginfantsagainst RSV-related hospitalizationin their first season of potential exposure to the virus.
The study looked at 699 infants from October 2023 through February 2024 using early data from CDCs New Vaccine Surveillance Network (NVSN), a population-based surveillance platform that monitors pediatric respiratory viruses to assess immunization effectiveness. Results show that nirsevimab was 90% effective at preventing RSV-associated hospitalization in infants during their first RSV season. These results reflect a shorter surveillance period due to the introduction of this new product in August 2023. Nirsevimab effectiveness may be lower over a full RSV season (October through March in most of the United States). With increasing availability of nirsevimab in future RSV seasons, CDCwill assess its effectiveness over an entire season.
RSV prevention products remain our single most important tool to protectinfants from RSV. Healthcare providers should recommendeither:
CDCcontinues to monitorthe safety andeffectivenessof nirsevimab and maternal RSV vaccines.
7 March 2024
Image source, Getty Images
There is a worrying rise in whooping cough, officials warn, with 553 cases in England recorded in January alone and high numbers in Wales.
They fear it could be a bumper year for the bacterial infection. The last peak year, 2016, saw 5,949 cases in England.
Known as pertussis or "100-day cough", the infection can be particularly serious for babies and infants.
And The UK Health Security Agency warns of a steady decline in uptake of the vaccine in pregnant women and children.
In September 2023, the number of two-year-olds who completed their routine six-in-one vaccinations, which includes protection against pertussis, was 92.9%, compared with 96.3% in March 2014.
Uptake of the maternal pertussis vaccine, offered to women in every pregnancy, also dropped - from over 70% in September 2017 to about 58% in September 2023.
The first signs of whooping cough are similar to a cold, with a runny nose and sore throat.
But after about a week, the infection can develop into coughing bouts that last a few minutes and are typically worse at night.
Young babies may also make a distinctive "whoop" or have difficulty breathing after a bout of coughing.
The bacteria spread through coughs and sneezes, so experts advise members of a family in which it has been diagnosed to stay at home until three weeks after the symptoms began or 48 hours after the patient started taking antibiotics.
NHS England national director for vaccinations and screening Steve Russell said: "With whooping cough on the rise, it is important that families come forward to get the protection they need.
"If you are pregnant and have not been vaccinated yet or your child is not up-to-date with whooping cough or other routine vaccinations, please contact your GP as soon as possible.
"And if you or your child have symptoms ask, for an urgent GP appointment or get help from NHS 111."
By Emily Stearn, Health Reporter For Mailonline 18:04 07 Mar 2024, updated 18:08 07 Mar 2024
Health officials today begged parents to get their children vaccinated amid spiralling cases of whooping cough.
Experts blame the resurgence of the '100-day cough' on a slump in vaccine uptake among kids and mothers-to-be, as well as a post-Covid resurgence caused by less immunity due to pandemic social distancing.
UK Health Security Agency (UKHSA) bosses received 553 lab-confirmed reports of whooping cough cases in England alone in January.
It marks a 61-fold rise on the nine logged over the same month in 2023 and comes after MailOnline earlier this year revealed that cases of whooping cough were at a decade high.
For comparison, there were 858 cases recorded in total last year.
Health officials warned the infection is initially difficult to tell apart from a cold, with the first signs typically being a runny nose and sore throat.
But around a week later, sufferers may develop coughing bouts which last minutes, struggle to breathe after coughing and make a 'whoop' sound between coughs.
Other signs of pertussis, as it is medically known, include bringing up a thick mucus that can cause vomiting and becoming red in the face.
UKHSA surveillance figures show, of the 553cases confirmed in January, more than half (287) were among those aged 15 years or older.
Just under a third (29.1 per cent) were in children aged 10 to 14 (161).
Whooping cough is caused by the pertussis bacteria and is spread by coughing and sneezing.
The infection is initially difficult to tell apart from a cold, as the first signs are a runny nose and sore throat.
But around a week later, sufferers may develop coughing bouts that last minutes, struggle to breathe after coughing and make a 'whoop' sound between coughs.
Other signs of whooping cough include bringing up a thick mucus that can cause vomiting and becoming red in the face.
Sufferers are infectious from around six days aftercold-like symptoms develop to three weeks after their cough starts.
Doctors dish out antibiotics as treatment if the whooping cough is detected within three weeks. However, if a person has been infected for longer, antibiotics will not speed up their recovery.
The infection can be fatal, with up to 3 per cent of newborns dying from it, according toProfessor Paul Hunter, an expert in infectious diseases from the University of East Anglia.
Additionally, most babies under six months with whooping cough are hospitalised with complications, such as dehydration, breathing difficulties and pneumonia.
It is less severe in older children and adults but can still cause sore ribs, a hernias, ear infections and urinary incontinence among these groups.
The 6-in-1 vaccine, given to babies at eight, 12 and 16 weeks, and the 4-in-1 pre-school booster, administered to children aged three years and four months, is vital for protecting against catching whooping cough.
Pregnant women are also encouraged to get the vaccine to protect their baby from catching the infection in the first few weeks of their life.
Some 22 infants aged under three-months, who are too young to be fully vaccinated, were also diagnosed.
The 6-in-1 vaccine, given to babies at eight, 12 and 16 weeks, and the 4-in-1 pre-school booster, administered to children aged three years and four months, is vital for protecting against catching whooping cough.
Pregnant women are also encouraged to get the vaccine to protect their baby from catching the infection in the first few weeks of their life.
Parents have been urged to check their kids have had both jabs.
Without the jabs, experts warn people risk becoming seriously ill from the infection and passing it on to others.
However, uptake of the 6-in-1 vaccine (92.6 per cent) and 4-in-1 jab (83.3 per cent) both slumped to all-time lows in 2023, according to NHS England data.
Meanwhile, just 61.5 per cent of expectant mothers had the whooping cough jab in 2022 the smallest number in seven years.
Dr Gayatri Amirthalingam, UKHSA's consultant epidemiologist at UK Health Security Agency, said: 'Whooping cough can affect people of all ages but for very young infants, it can be particularly serious.
'However, vaccinating pregnant women is highly effective in protecting babies from birth until they can receive their own vaccines.
'Parents can also help protect their children by ensuring they receive their vaccines at the right time or catching up as soon as possible if they have missed any.
'If you're unsure, please check your child's red book or get in touch with your GP surgery.'
Steve Russell, national director for vaccinations and screening at NHS England, added: 'With whooping cough on the rise, it is important that families come forward to get the protection they need.
'If you are pregnant and have not been vaccinated yet, or your child is not up-to-date with whooping cough or other routine vaccinations, please contact your GP as soon as possible, and if you or your child have symptoms ask for an urgent GP appointment or get help from NHS 111.'
Whooping coughis caused by the pertussis bacteria and is spread by coughing and sneezing.
Doctors dish out antibiotics as treatment if the whooping cough is detected within three weeks.
However, if a person has been infected for longer, antibiotics will not speed up their recovery.
Pre-pandemic, between 2,500 and 4,500 suspected cases were logged each year. This fell to around 500 during thecoronavirus crisis as social distancing curbed the spread of most bugs.
But cases hit 1,728 in 2023 because of the post-pandemic rebound, in a trend that experts say is down to lower societal immunity as a result of the Covid era.Similar trends were seen for bugs like flu and RSV.
However, rates are still nowhere near the annual high of 170,000 logged in the 1940s. Routine vaccination against whooping cough in the 1950s dramatically slashed levels.
Health officials also acknowledgedcases of whooping cough rise cyclically every few years. The last peak year 2016 logged 5,949 cases.
Vaccines for babies under 1 year old
8 weeks
12 weeks
16 weeks
Vaccines for children aged 1 to 15
1 year
2 to 15 years
3 years and 4 months
12 to 13 years
14 years
Source: NHS Choices
