Kate O'Brien, Director of the Department of Immunization, Vaccines and Biologicals at WHO
In a pivotal meeting last month, the Strategic Advisory Group of Experts on Immunization (SAGE) came together to examine comprehensive global and regional reports on immunization programme and outbreak status on immunization programme and outbreak status, thoroughly explore the progress on Immunization Agenda 2030 (IA 2030) goals, and offer vital recommendations regarding polio, hepatitis E, and Mpox vaccines.
The meeting also celebrated the 50th anniversary of the Expanded Programme on Immunization (EPI), recognizing its monumental achievements since its founding in 1974, while charting a course for its future endeavors. Over the past five decades, immunization has emerged as a cornerstone of primary healthcare, community development, and global health, by significantly impacting child survival rates through largescale prevention of vaccine-preventable disease and mortality. EPI has not only created the foundations of primary healthcare in many countries but has also played a vital role in promoting equity in healthcare access.
The meeting highlighted the remarkable advancements in vaccine technologies and distribution mechanisms, which have led to the development and deployment of numerous life-saving vaccines.
However, amidst the celebration of past accomplishments, SAGE also acknowledged recent setbacks, particularly in meeting the goals outlined in the IA 2030. While preliminary data from 2023 show increasing signs of recovery towards pre-pandemic vaccination levels, there remains much work to be done to realign efforts with the Agendas objectives. Looking ahead, SAGE emphasized the importance of country ownership, community-centered approaches, partnership building, and data-driven decision-making without which the goals of IA 2030 will not be achieved.
The meeting also addressed the implementation progress of the Big Catch-up initiative, stressing the necessity of political commitment, community involvement, and healthcare workforce capacity building. Monitoring the initiative's progress through robust data collection and analysis was deemed essential for informing future actions and ensuring accountability. Recognizing the challenges in data collection and surveillance systems, SAGE emphasized the need for long-term investments in strengthening immunization data capacity and infrastructure.
As the world continues to navigate health challenges and polycrises, SAGE reaffirmed its commitment to advancing immunization efforts worldwide, guided by evidence-based strategies and a collective resolve to safeguard public health.
EYE Strategy Annual Partners' Meeting 2024
The convening served as a platform to commend and extend support to Ethiopia for its recent decision to incorporate the yellow fever vaccine into its routine immunization schedule nationwide, a strategic move aimed at bolstering the country's defenses against this potentially devastating disease. Additionally, the gathering aimed to strategize and mobilize resources for the implementation of preventive mass vaccination campaigns, crucial steps in curbing the spread of yellow fever.
Amidst discussions and exchanges of insights, the meeting celebrated a monumental achievement: the protection of more than 365 million individuals across Africa against yellow fever since the inception of the EYE Strategy. Of these, over 264 million people have been safeguarded through extensive vaccination campaigns, underscoring the efficacy and impact of concerted efforts in disease prevention and control.
However, the convening also shed light on the sobering reality of the resurgence of yellow fever outbreaks in regions that have historically benefited from preventive mass vaccination campaigns. Comprehensive analyses were presented, prompting a collective commitment among partners and stakeholders to implement catch-up interventions and strengthen routine immunization programs for yellow fever vaccination and beyond.
Furthermore, partners and key stakeholders reflected on the EYE Strategy's trajectory, recognizing that it has entered an accelerated phase following an independent mid-term evaluation. This phase necessitates a renewed and intensified commitment from all involved parties to ramp up activities related to yellow fever prevention and control until the Strategy's formal conclusion in 2026.
The EYE Strategy Annual Partners' Meeting 2024 underscored the importance of proactive measures, solidarity among nations, and sustained investment in public health initiatives to safeguard communities worldwide from the life-threatening consequences of infectious diseases.
Measles and Rubella Partnership ignites action
The Measles and Rubella Partnership (M&RP) also held a series of leadership and partnership meetings in Washington DC in March, with a focus on achieving a measles and rubella-free world. Over 150 global participants gathered for the first time since 2019, to ignite discussions on breaking through bottlenecks, broaden horizons, and tackle challenges head-on in pursuit of the strategy goals for measles and rubella elimination.
The meeting concluded with a call-to-action, urging increased ownership and collaboration, proactive efforts to close immunity gaps, adoption of innovative approaches, amplified investments in cutting-edge technologies, and a commitment to sustaining and accelerating our collective efforts towards achieving our measles and rubella eradication goals.
With determination, the M&RP community marches forward, fueled by the belief that together, we can build a world free from the threat of measles and rubella.
For the first time, cervical cancer's end is in sight
March brought monumental progress in the fight against cervical cancer, signaling that the end of this deadly disease is finally within sight. The first-ever "Global cervical cancer elimination forum: advancing the call to action" held from March 5th to 7th, in Cartagena de Indias, Colombia, served as a game-changing platform. Governments, donors, multilateral institutions, and partners converged to champion the global elimination strategy and address the stark inequities denying women and girls access to life-saving interventions.
Despite having all the necessary tools to prevent and eliminate cervical cancer, the disease continues to wreak havoc on hundreds of thousands of women, families, and communities worldwide. Access to vaccines, screening, and treatment remains woefully inadequate in the most vulnerable regions. Vaccines, crucial in preventing human papillomavirus (HPV) infections and subsequently cervical cancer, are not reaching those who need them the most.
However, hope soared as unprecedented commitments were announced at this landmark forum, totaling nearly US$600 million in new funding to eradicate cervical cancer. These commitments, aimed at expanding vaccine coverage and strengthening screening and treatment programs, could potentially mark the first-ever elimination of a cancer. This momentum builds upon the promise made in 2020 when 194 countries adopted WHO's global strategy to eliminate cervical cancer.
With bold commitments and decisive action, the focus now shifts to accelerating progress and supporting countries in their journey towards equitable access to care. Together with partners, efforts are underway to pave the way for a future where all women, regardless of socio-economic status or geographic location, have access to the care they deserve.
Combatting malaria: a call to action in Africa's high-burden countries
Despite progress, malaria continues to claim lives and devastate families, with the African region bearing the brunt of the burden, representing 94% of global malaria cases and 95% of global deaths.
The conference culminated in the signing of a declaration by ministers committing to stronger leadership and increased domestic funding for malaria control programs. The pledge includes further investment in data technology, application of latest technical guidance, and enhancement of efforts at national and sub-national levels.
To reignite progress against malaria, greater domestic and international funding, science-driven responses, research, and innovation are imperative. With political leadership, country ownership, and collaborative partnerships, the story of malaria in Africa can be rewritten for the betterment of families and communities continent-wide
April's global health milestones: promoting immunization efforts
April is set to host two significant events aimed at advancing global health initiatives and promoting immunization efforts.
Firstly, WHO is gearing up for its inaugural high-level meeting to combat meningitis. Scheduled to take place in Paris on April 26, this meeting aims to mobilize commitments towards achieving the objectives outlined in the WHO Global Road Map to defeat meningitis by 2030. With a focus on galvanizing support and resources, the meeting signals a crucial step towards eliminating meningitis epidemics and caring for those who suffer the long-term consequences of meningitis.
Additionally, April 24-30 will see the celebration of World Immunization Week, a rallying call to ramp up investments in immunization programs, and in so doing, ensuring the protection of future generations against deadly infections. The central theme this year will be the 50th anniversary of the EPI, highlighting the commitment of the global community to prioritize public health and strengthen immunization efforts, underscoring the importance of collective action in achieving health equity and resilience. The theme this year will be Humanly Possible and we welcome all of you to plan for how you will mark this week and contribute to the social movement of immunization. Please visit the World Immunization Week 2024 portal where all the social media assets and more information on activities during the week will be available by mid-April. Take part, join in, and add your voice.
By building on the foundation of past successes, we can assure that vaccines continue to save ever more lives each year. Through sustained investment, collaboration, and a shared commitment to vaccines and immunization programmes, we can harness the full potential of these life-saving products to protect individuals, communities, and future generations from preventable diseases.
Let us take this unique moment of 50 years of country immunization programmes to reaffirm the evidence on their crucial role in the health of people across all ages and especially their role to protect the adult in every child.Vaccines have an indispensable role in safeguarding human health and well-being worldwide.
----
Click here to subscribe to the Global Immunization Newsletter.
Last month, the Centers for Disease Control and Prevention issued awarningover the increase in measles outbreaks. And this week, the Chicago Department of Public Health warned about possible measles exposure at several city locations.
While measles is most dangerous for young children and pregnant women, the CDC warns everyone especially those planning international travel of any kind should get vaccinated to prevent the virus spread.
As far as who does not need the MMR Vaccine, the CDC lists the following criteria:
Additionally, the CDC says, if you received a measles vaccine in the 1960s, you may not need to be revaccinated.
Those who received the vaccine in the 1960s should check their vaccine records. If you received the LIVE measles vaccine in the 1960s, the CDC says you do not need to be revaccinated.
The killed measles vaccine is an earlier formulation of measles vaccine that is no longer used. The CDC says if your vaccine documentation indicates you received the killed measles vaccine, you should talk with you healthcare provider about getting revaccinated with the current MMR vaccine.
The CDC says this recommendation is intended to protect those who may have received killed measles vaccine, which was available in 1963-1967 and was not effective.
Additionally, according to the CDC, being before 1957 provides only presumptive evidence for measles, mumps, and rubella. Before vaccines were available, nearly everyone was infected with measles, mumps, and rubella viruses during childhood. The majority of people born before 1957 are likely to have been infected naturally and therefore are presumed to be protected against measles, mumps, and rubella. Healthcare personnel born before 1957 without laboratory evidence of immunity or disease should consider getting two doses of MMR vaccine.
More than 16,000 troops sought waivers. Just 339 were granted.
NORFOLK, Va. There are new questions about how the military handled thousands of cases where service members refused the COVID-19 vaccine because of "sincerely held religious beliefs."
A Marchreport from the Defense Department Inspector Generalfound that while the military branches largely followed policy when considering waivers for service members who sought religious exemptions from having to take the COVID-19 vaccine, the Army and Air Force did not meet the DOD time guidelines in processing those requests.
The Army has a 90-day deadline for processing requests but, the cases averaged 192 days to receive a decision.
In the Air Force, requests averaged 168 days to adjudicate, despite the deadline being 30 days.
Concerns raised by impacted service members prompted multiple lawsuits alleging that the DOD and service branches were blanketly denying religious waiver requests.
"That demonstrates outright religious hostility. That is afford to the Constitution and federal law." First Liberty Institute attorney Mike Berry told 13 News Now in January 2022.
Overall, the numbers are eye-opening. Of more than 16,000 religious exemption requests received, just 339 were approved. 13,387 were denied.
According toDefense Department statistics, more than 2 million military members did get their COVID shots.
But, according to the Associated Press over 8,400 troops were discharged due to non-compliance.
WASHINGTON -- The benefits of combination vaccines may seem obvious (fewer visits, less discomfort), but their development for adults is not without challenges, pharmaceutical company experts said at the World Vaccine Congress on Wednesday.
Combination vaccines have been available for children for decades, but whether they're also needed for adults, and for which viruses, have been debated.
"I think combination vaccines have the potential for enormous public health benefit," said Kayvon Modjarrad, MD, PhD, executive director of vaccine research and development for Pfizer.
In addition to the convenience of fewer shots and fewer sore arms, combination vaccines have the potential to reduce the burden of vaccination on the overall healthcare system and improve equity, he noted.
Francesca Ceddia, MD, chief medical affairs officer for Moderna, said another perk of combined vaccines is the potential to increase coverage rates.
Despite rates of hospitalizations and deaths from COVID-19 being two to five times higher than those for influenza, people don't question flu vaccines the way they do COVID vaccines, Ceddia said, adding that she anticipates that a combination COVID/flu vaccine could help normalize COVID vaccination.
"People do not question why [they] should get diphtheria, tetanus, pertussis, etc.," she pointed out.
Ceddia also highlighted the potential to increase vaccine uptake for lesser known illnesses -- for example, by pairing vaccination for respiratory syncytial virus (RSV) with human metapneumovirus (HMPV).
The primary criteria for pairing two diseases in one vaccine is to have overlapping epidemiology and indications, the panelists said.
In the case of RSV and HMPV, both are respiratory pathogens that affect the upper and lower respiratory tracts, and both impact a similar population -- young children and older adults, Ceddia told MedPage Today in a follow-up email, adding that HMPV is "very similar" to the antigen for RSV.
The viruses also have matching seasonality and a similarly underestimated burden of disease, even more so for HMPV, she said. Moderna is working on such a vaccine and to date has completed phase I trials in pediatric populations.
Looking at less ideal combinations, duration of protection matters. It's unclear how long the current RSV vaccine will protect people, but if that duration is longer than for COVID or flu, pairing RSV with either gets increasingly more complicated. "This is what we're learning," Ceddia said, based on data that are currently being collected.
Piyali Mukherjee, MPH, vice president and head of global medical affairs, vaccines, for GSK, also noted that she sees clear benefits from combination vaccines in adults, and "with so many new technologies -- mRNA, mAbs [monoclonal antibodies] -- I'm sure this space will only grow."
Robert Walker, MD, chief medical officer for Novavax, was more skeptical.
In considering the "value proposition" of combination vaccines for adults, one should look at the injection burden and current vaccine schedule, he said. Children receive approximately 27 separate injections in their first 2 years, with as many as six in one visit.
"Clearly, there's an injection burden there, and there's a medical need," he said. "Do we have the same problem in the adult sector?"
Walker also challenged the idea that a combination flu/COVID vaccine might improve COVID vaccination uptake.
"Equally possible is that the COVID [vaccine] could be pulling the flu acceptance down," he said.
However, a 2023 meta-analysis suggested the opposite: that combining flu vaccines and COVID boosters "can be an effective strategy for increasing the uptake of the latter by populations that have shown reluctance against taking it," the authors wrote.
Ceddia is confident that the negativity and misconceptions around COVID vaccines will dissipate, she told MedPage Today, especially as awareness that vaccination prevents not only acute symptoms but also long COVID increases.
Furthermore, reducing the number of visits for vaccine administration "saves cost and time," she added. "If we assume [combination vaccines] could potentially increase compliance and adherence to vaccination, and improve coverage rates, there would be savings in terms of healthcare cost utilization."
Panelists were also asked about other specific challenges in development, including the potential for immune interference -- the belief that the immune system can become overloaded with simultaneous exposures to more than one vaccine -- and the "upper limit of toxicity" (the point at which increasing the dose of a vaccine changes the adverse event profile).
Modjarrad stressed that these are important considerations. There are already inherent complexities to developing a combination COVID/flu vaccine. For instance, there are multiple antigens present in the flu vaccine itself, which is why Pfizer is taking a "very deliberate, phased approach to this," and starting with two vaccines, not four or five, he said.
Mukherjee added that some immune interference is to be expected. That's why it's important to know what level of interference actually matters, then do studies and collect the data, she said.
As for vaccine reactogenicity, "this is where platform optimization will become very, very important," she noted. In early studies of GSK's partnership with CureVac, for example, "even at the highest dose ranges [that were tested], you do have a much lower level of reactogenicity."
Walker said that Novavax has seen interference between flu and COVID in phase II studies using recombinant protein nanoparticle platform technology, and therefore increased the amount of antigen, but the platform "can accommodate a lot of antigen."
"As we drive up antigen, our experience has been that the reactogenicity is indistinguishable from the lowest antigen dose levels," he said.
Also, as Ceddia pointed out, regulators are quick to remind companies that if a vaccine doesn't perform in the same way as the original, it's unlikely to move forward.
"It's a very complex field," she said, but knowing what has worked in the pediatric space, "there is reason to believe that it could also work in the adult space."
Shannon Firth has been reporting on health policy as MedPage Today's Washington correspondent since 2014. She is also a member of the site's Enterprise & Investigative Reporting team. Follow
gE antigen design, expression, and characterization
Since glycoprotein E (gE) is the most abundantly expressed antigen both on the surface of the varicella zoster virus (VZV) particles and on the infected cells24 and is used in the currently approved subunit vaccine Shingrix16, we therefore designed our mRNA constructs to encode this protein. gE is a transmembrane protein consisting of a long N-terminal extracellular domain expressed on the cell or viral surface, a short transmembrane domain anchoring the protein to the viral or host cell membrane, and a short C-terminal cytoplasmic domain. The N-terminal extracellular domain mediates its binding to insulin-degrading enzyme (IDE) on the cell surface26 and represents the main VZV antigen for recognition by antibodies and T-cells. The C-terminal domain has been shown to play a critical role in gE protein localization, however, the relationship between localization of the membrane protein and immunity is poorly understood. Therefore, our experimental designs for selection of a particular gE antigen-encoding mRNA candidate were based on comparison of the full-length gE antigen to its truncated variants. Specifically, we designed three versions of the gE antigen (Fig. 1A): (i) full-length gE (gE full-length), as present on the surface of the virion or naturally infected cells24, (ii) truncated gE (gE truncated), generated by deleting a part of the C-terminal domain and including a single amino acid substitution (Y569A) altering one of the trans-Golgi network (TGN) localization motifs, as described previously25, and (iii) soluble gE (gE-soluble), which is expressed as the extracellular domain of the protein and similar to the antigen sequence in Shingrix. In truncated gE, the C-terminal domain containing the trans-Golgi network (TGN) localization motif was modified by a single point-mutation: AYRV to AARV (Y569A). These modifications were made in truncated gE with the aim to address gE trafficking and thus potentially improve the surface expression of gE after translation. In addition to a codon-optimized open reading frame, the mRNA also contained a proprietary transcription initiation sequence (TIS), human -globin (HBG) 5 UTR and 3 UTR sequences, and a polyA tail sequence. The final transcript was 5 capped and contained N1-methylpseudouridine (m1) modified bases.
A Schematic representation of the various domains of VZV gE. The N-terminal domain contains disulfide bonds, N-glycans, and O-glycans (O-glycans not shown). Three versions of the VZV gE protein that we designed are shown: The soluble gE protein (gE soluble) contains only the signal sequence (SS) and the extracellular N-terminal domain. The truncated gE protein (gE truncated) contains the signal sequence, extracellular N-terminal domain, transmembrane (TM) domain and part of the C-terminal domain with one point mutation in the trans-Golgi network (TGN) localization motif, wherein AYRV sequence was modified to AARV (Y569A). The full-length gE protein (gE full-length) contains the entire wild-type open reading frame of the glycoprotein. B Western blot of cell lysates (left) and cell supernatants (right) after transfection with the indicated gE-expressing mRNA constructs. gE-FL gE full-length, gE-T gE truncated, and gE-SgE soluble protein. Red bands correspond to the gE protein, green bands correspond to beta actin that is used as loading control. The observed molecular weight sizes for gE-FL (90kDa) and gE-T (80kDa) correspond to their partially glycosylated forms. gE-S (observed at 75kDa) is not detected in the cell lysates, as expected, but is instead detected in the supernatant (right). C, D Detection of gE expression on cell surface (gE full-length and gE truncated) and in supernatant (gE soluble) by ELISA. EC50 values (in nM) are shown as MeanSD; R square values are shown to highlight the goodness of fit. The detection is performed using anti-gE antibodies. E, F Binding of human Fc fragment to cell surfaces expressed gE (gE full-length and gE truncated) (E) and gE in supernatant (F) to demonstrate the appropriate conformation and functional nature of the gE proteins. EC50 values (in nM) are shown as MeanSD; R square value is shown to highlight the goodness of fit.
After generation of the mRNA constructs, we successfully demonstrated the expression of all three gE variants in transfected HEK293FT cells by Western blotting (Fig. 1B) and in transfected HeLa cells by in-cell ELISA (for gE full-length and gE truncated; Fig. 1C) and supernatant ELISA (for gE soluble; Fig. 1D). The various gE proteins migrated on the PAGE gel at expected molecular weights with a clear difference between the sizes of the full length and truncated (gE truncated and gE soluble) versions of the protein. As expected, the soluble gE was not detected in cell lysates but was detected in the supernatants of transfected cells both by Western blot (Fig. 1B) and by ELISA (Fig. 1D). In-cell ELISA (gE full-length and gE truncated) and ELISA (gE soluble) showed that the expression levels of full-length gE and truncated gE antigens (Fig. 1C) were similar to the soluble gE antigen (Fig. 1D). This was further confirmed when HEK293FT cells, expressing the three gE antigen variants, were treated with Brefeldin A and we observed similar expression levels via Western blot (data not shown). Additionally, we characterized the functionality of the expressed gE proteins by their ability to bind human Fc. To that end, we developed Fc-binding ELISAs and observed that all three gE variants bound the recombinant human Fc similarly (Fig. 1E for gE full-length and gE truncated antigens binding to Fc; Fig. 1F for gE soluble antigen binding to Fc). These results confirmed the successful designs of the mRNA constructs encoding the three gE antigen variants, their appropriate expression upon transfection, and demonstration of functional antigenic conformation via human Fc-binding.
To generate vaccine candidate materials for the in vivo studies, the three gE-encoding (gE full length, gE truncated and gE soluble protein) mRNAs were produced by in vitro transcription, purified using lithium chloride precipitation, and stored at 65C until further use. The purified mRNAs were tested for the following key attributes: concentration, identity, purity/integrity, poly(A) tail length, % capping efficiency, % N1-methyl-pseudouridine (m1) incorporation, and levels of various impurities (e.g., RNase, endotoxin, E.coli DNA and residual NTPs). These analytical test results are shown in Supplementary Table S2. Thereafter, all three purified gE-encoding mRNAs were encapsulated in either NOF-lipid-based LNPs or SM102-lipid-based LNPs and the final formulated mRNA-LNPs were tested for the following critical attributes: Particle size, Polydispersity index (PDI), % mRNA encapsulation, % mRNA purity post encapsulation and mRNA concentration. The analytical test results of the six mRNA-LNPs are shown in Supplementary Table S3.
We aimed to evaluate immunogenicity of the three gE-encoding GLB mRNA-LNP vaccine candidates in mice. However, before evaluating all three gE variants, we wanted to conduct a preliminary study using the mRNA-LNP formulation encoding the full-length glycoprotein E (gE). The LNP formulation was based on proprietary cationic lipids from NOF corporation. The aim of this preliminary study was to quickly test if the novel NOF-LNP formulation was effective in delivering the mRNA in vivo, using the gE full-length antigen, before conducting the full comparative evaluation of the gE variants. As positive control, the currently approved subunit vaccine Shingrix was used.
To mimic pre-existing immunity against VZV, which is expected to be present in dormant state in the target human population, C57BL/6 female mice were primed with a full human dose (500L) of the live-attenuated Varicella Zoster virus (Varivax) by subcutaneous administration. It should be noted that the live-attenuated VZV (Varivax) cannot replicate in mouse cells and establish latency in this animal. Mice were immunized with two intramuscular injections of the gE full-length encoding mRNA-LNP (NOF) candidate, 4- and 8-weeks post Varivax priming, as shown in Fig. 2A. Immunizations were performed at a dose of 5g per animal, in a total volume of 50L per mouse (25L in each hind limb). Mice injected with Varivax only or saline were included as controls.
Female C57BL/6 mice were primed with a full human dose of the live attenuated VZV vaccine (Varivax) by subcutaneous administration. Mice were then injected intramuscularly with 5g of mRNA-LNP vaccine candidates, expressing VZV gE full-length, or saline (Varivax only group) at weeks 4- and 8- post Varivax administration. NOF-LNP formulated mRNA, delivering gE full-length, is the test candidate while Shingrix is used as a positive control. A Scheme of immunizations and sample collections schedule. B End-point titers of gE-specific IgG binding antibodies detected in mice at the indicated timepoints and evaluated by ELISA. Arrows indicate the two mRNA-LNP/Shingrix immunization timepoints. Data shown as MeanSEM, and is representative of two independent experiments using 10 animals per group. Y-axis represents Log10 end-point titers; X-axis represents weeks post-Varivax prime. C Antigen-specific effector T cell responses measured from whole blood using a murine IFN-/IL-2 Double-Color Enzymatic ELISpot Assay. Data shown as MeanSEM. Y-axis represents Spot Forming Cells (SFCs) per million peripheral blood cells. Each SFC corresponds to an effector T cell secreting either one or both cytokines in response to stimulation by the gE overlapping peptides pool.
Anti-gE IgG binding antibodies were detected by ELISA from serum samples collected at 0-, 4-, 6-, 8-, and 10-weeks post Varivax prime. Immunization of mice with 5g of gE full-length mRNA-LNP (NOF) induced high levels of anti-gE serum IgG binding antibodies that were comparable to those elicited by Shingrix, as shown in Fig. 2B. Anti-gE binding antibody titers observed in animals immunized with mRNA-LNP (NOF) vaccine increased significantly after each immunization, when compared to animals primed with Varivax only.
Effector T cell responses were assessed from peripheral blood 2 weeks post Varivax prime (baseline response), and 1 week post the first and second mRNA-LNP immunizations using the murine IFN-/IL-2 Double-Color Enzymatic ELISpot Assay. gE-specific activated T cells secreting either IFN- or IL-2 or both cytokines, after re-stimulation with gE overlapping peptides, were quantified (Fig. 2C). At baseline, the number of spot-forming cells (SFC) in all groups were similarly low, below 10 SFC per million blood cells. However, following two immunizations with 5g of mRNA-LNP (NOF) vaccine candidate, all animals developed strong gE-specific effector T cell responses that were higher than those observed in mice administered with two injections of Shingrix. No long-lasting T-cell response was detected in animals primed with Varivax alone. Taken together, the data from this preliminary study shows that the GLB mRNA-LNP (NOF) formulation is successful in delivering the gE glycoprotein and successful in eliciting a strong immunogenic response, comparable to Shingrix, in mice.
Based on the success of the above preliminary in vivo study in mice, we designed this expanded comparative immunogenicity study to evaluate all three mRNA-LNP vaccines candidates, encoding the three different versions of the gE antigen, and to compare them to Shingrix. For this study, the three gE antigen variants-encoding mRNAs were formulated in two different LNP formulations for in vivo testing: one using the proprietary NOF LNP and the other using SM102 LNP, as a LNP comparator. SM102 LNP was chosen as a comparator because successful delivery of mRNA encoding for VZVs gE by SM102 LNP has been reported earlier by Monslow et al.27. Each mRNA-LNP candidate was produced, tested for critical attributes (mRNA content, mRNA integrity and purity, LNP size and polydispersity) and thereafter frozen at <65C until use in the study. In this study, two different antigen doses for each of the gE antigens were tested: a high dose of 5g and a low dose of 1g.
Consistent with the previous mouse study (Fig. 2A), this study in C57BL/6 female mice was also similarly designed. All mice received a full human dose (500L) of the live attenuated Varicella vaccine (Varivax) by subcutaneous administration to set the initial VZV infection. 4 weeks post Varivax priming, mice were administered with two intramuscular injections of the formulated mRNA, 4 weeks apart (Fig. 3A). Additionally, one group of mice was administered with 5g of Shingrix (1/10 of the human dose) twice, 4 weeks apart, as positive control or an active comparator. Vaccines were administered in a total volume of 50L per mouse (25L in each hind limb). Mice injected with Varivax only and saline were included as (negative) controls.
Female C57BL/6 mice (5 animals per group) were primed with a full human dose of the live-attenuated VZV) vaccine (Varivax) by subcutaneous administration. Mice were then injected intramuscularly with 1 or 5g of mRNA-LNP vaccine candidates, encoding the three gE variants, or saline (Varivax only group) at 4 and 8 weeks post Varivax administration. A Scheme of immunization and sample collection schedule. B Longitudinal Log10 end-point titers (Y-axis) of gE-specific IgG binding antibodies detected in sera collected from mice at the indicated timepoints and evaluated by ELISA. Arrows indicate mRNA-LNP/Shingrix immunization time points. Data shown as MeanSEM. C Quantitative assessment of anti-gE serum IgG binding antibodies in mice from all vaccinated groups at 12 weeks post Varivax prime, assessed by ELISA and expressed as area under the curve (AUC) (Y-axis) based on absorbance values. Data shown as MeanSEM.
Anti-gE binding antibodies were detected by ELISA from sera of mice collected on 0, 4, 8, 12, 16, 20, and 24 weeks. Serum IgG binding antibody levels induced by NOF LNPs encapsulating 5g of mRNA were equivalent to antibody levels observed in animals vaccinated with Shingrix (Fig. 3B). Moreover, NOF LNP-formulated vaccine induced higher levels of gE-specific binding antibodies when compared to SM102 LNP-formulated vaccines in a dose-dependent manner (Fig. 3C). The peak binding antibody response was observed at week 12 i.e., 4 weeks post 2nd vaccination (Fig. 3B, C). As expected, mice vaccinated with saline had no detectable anti-gE serum IgG throughout the study.
Previous studies suggest that CD4+ T cells play a critical role in protecting against reactivation of VZV28,29. The decline in VZV-specific CD4+ T-cell responses has been associated with an increased risk of herpes zoster in older adults30,31. Moreover, immunocompromised individuals with impaired CD4+ T-cell function, such as people living with HIV, but not antibody deficiencies, are at a higher risk of developing herpes zoster and are more likely to experience severe and prolonged episodes28. Therefore, vaccines that can boost CD4+ T cell responses are believed to provide additional protection against reactivation of VZV. To that end, to assess amplitude and kinetics of T cell responses induced by the various mRNA-LNP vaccines encoding the three gE antigen variants, peripheral blood was collected 2 weeks post Varivax prime, and at 1 and 2 weeks post each vaccination (mRNA-LNP or Shingrix), as depicted in Fig. 3A. Peripheral blood mononuclear cells were stimulated with a gE overlapping peptide pool, and the number of gE-specific cells secreting IFN- and/or IL-2 was quantified by dual-color ELISpot. Priming with Varivax induced very weak T-cell responses in mice (Fig. 4A), as also previously described by others19,27. Effector T cell responses peaked at day 7 post each vaccination, either by the mRNA-LNP vaccines or the active control (Shingrix). Overall, the mRNA-LNP vaccine expressing the soluble version of gE performed poorly when compared to mRNA-LNP vaccines encoding the full-length gE or the truncated gE; regardless of the type of LNP (NOF vs. SM102) formulation used (Fig. 4A, B). Remarkably, the three NOF LNP-formulated vaccines encoding each of the three gE antigen variants, induced very high levels of poly-functional effector T cells, evidenced by secretion of more than one cytokine simultaneously, which were higher than levels induced by the Shingrix vaccinated animals.
A, B Female C57BL/6 mice (5 animals per group) were primed with a full human dose of the live attenuated VZV vaccine (Varivax) by subcutaneous administration. Mice were injected intramuscularly 5g of the mRNA-LNP vaccine candidates, expressing the three gE variants, or Shingrix at 4 and 8 weeks post Varivax administration. A, B Antigen-specific effector T cell responses were measured from whole blood cells collected at week 5 i.e., 1 week post 1st immunization (A) or week 9, i.e., 1 week post 2nd immunization (Busing a murine IFN-/IL-2 Double-Color Enzymatic ELISpot Assay. Data shown as MeanSEM. Y-axis in both panels, A and B, represents Spot Forming Cells (SFCs) per million peripheral blood cells. Each SFC corresponds to an effector T cell secreting either one or both cytokines in response to the gE overlapping peptides pool.
To bolster the above findings, we conducted an additional study to measure effector T cell responses from splenocytes, collected 1 week post 2nd immunization with mRNA-LNP (NOF), mRNA-LNP (SM102) or Shingrix, by intracellular cytokine staining (ICS). In this study, mice were administered with two intramuscular injections of the LNP (NOF or SM102) formulated mRNA or Shingrix, 4 weeks apart, without Varivax priming (Fig. 5A). Mice injected with saline were included as (negative) controls. Splenocytes obtained a week after the second immunization were stimulated with gE overlapping peptide pool, and the number of gE-specific CD4+ or CD8+ T cells secreting IFN-, TNF- and/or IL-2 were quantified by flow cytometry (Supplementary Figure S1). The gE-specific effector T cell responses were predominantly CD4+ T cell-mediated, since less than 0.5% of the CD8+ T cells in the spleen detected were secreting cytokines upon stimulation with gE peptides (Fig. 5B and Supplementary Figure S2A). Administration of NOF or SM102 formulated mRNA-LNP vaccine candidates induced potent CD4+ T cell responses, as seen by the number of gE-specific CD4+ T cells secreting either one, two or all three of the cytokines IFN-, TNF- and IL-2 (Fig. 5C and Supplementary Figure S2B). Importantly, both NOF and SM102-formulated mRNA-LNP vaccines induced higher levels of CD4+ T cell responses than Shingrix.
A Animals were divided in groups of 7, and subsequently immunized with 2 intramuscular doses, 4 weeks apart, of gE mRNA-LNP (NOF or SM102) or Shingrix. Mice injected with saline were included as negative controls. One week after the last immunization, spleens were harvested and stimulated with overlapping peptide pools from VZV gE protein, and percentage of CD8+ (B) and CD4+ (C) T cells producing IFN-, TNF-, and IL-2, was measured by flow cytometry.
Effective vaccines are expected to generate adaptive immunological memory in the B cell (BMEM) and T cell (TMEM) memory compartments. This memory is crucial for rapid recall of the immune responses to avoid re-activation of VZV and causation of herpes Zoster disease27,32. To assess if vaccination with the gE antigen encoding mRNA-LNP vaccine candidates could lead to long-term persistence of humoral responses, the presence of gE-specific long-lived plasma cells was investigated in the bone marrows and effector memory CD4+ T cells in the spleens of mice, collected 16 weeks post 2nd immunization, as depicted in schematics on Fig. 3A. gE-specific long-lived plasma cells (LLPCs), quantified as the number of bone marrow-derived anti-gE antibody (IgG) secreting cells (ASC) by B cell ELISpot assay, induced by 5g of mRNA formulated with NOF LNP, were comparable to responses observed in animals vaccinated with Shingrix (Fig. 6A). Additionally, gE-specific CD4+ effector memory T cells, characterized as CD4+ CD44+ CD62L-, were quantified from spleens. We observed that gE-specific effector memory CD4+ T cell responses, induced by 5g of mRNA formulated with NOF LNP, were comparable to responses observed in animals vaccinated with Shingrix (Fig. 6B). Cumulatively, based on the overall gE-specific antibody titers, antigen-specific T cell responses and LLPCs and T cell memory results, we selected the gE full-length for future studies to support clinical development of this vaccine candidate.
C57Bl/6 mice (5 animals per group) were primed with live attenuated VZV vaccine (Varivax), and vaccinated twice, 4 weeks apart, with the mRNA-LNP vaccine candidates or Shingrix. Immunological memory was evaluated 16 weeks post last immunization. A Long lived plasma cells in the bone marrow secreting antibodies that bind to VZV gE, quantified by B cell ELISpot assay. Y-axis represents Spot Forming Cells (SFCs) per million bone marrow-derived cells. B Percentages of effector memory CD4+CD44+CD62L- T cells (Y-axis) secreting either IFN-, TNF-, and IL-2 alone or any of the two or all three cytokines. Data shown as MeanSEM.
Despite the high efficacy of Shingrix, vaccinees have reported severe local and systemic reactions post vaccination21,22. Thus, aware of the pronounced reactogenicity of Shingrix, one of our major goals was to develop a mRNA-LNP vaccine against herpes zoster that is at least comparable with respect to immunogenicity of Shingrix but with potentially lower induction of systemic inflammation.
To assess systemic inflammation induced by the selected gE full-length mRNA-LNP vaccine candidates, pro-inflammatory cytokines were measured from sera collected before immunization and 6h and 24h after the 1st immunization with mRNA-LNP (NOF) formulated vaccine candidate or mRNA-LNP (SM102) formulated vaccine candidate or Shingrix, using the LEGENDplex Mouse Anti-Virus Response Panel. Interestingly, both NOF and SM102 lipid-formulated mRNA-LNP vaccines induced significatively lower levels of pro-inflammatory cytokines such as MCP-1 (Fig. 7A), CXCL-1 (Fig. 7B), and CXCL-10 (Fig. 7C) post vaccination than Shingrix. Other pro-inflammatory cytokines such as interferons, IL-1 and IL-6 (that were included in the LEGENDplex Mouse Anti-Virus Response Panel) were not detected at any of the time points across all groups. These findings suggest that additional investigations will be necessary in future to allow for the full assessment of local and systemic toxicity of our mRNA-LNP in comparison to Shingrix.
Female C57BL/6 mice (7 animals per group) were immunized with 5g of either SM102 LNP-formulated mRNA encoding gE full-length or NOF LNP-formulated mRNA encoding gE full-length or Shingrix or saline alone (negative control). Pro-inflammatory cytokines (MCP-1 in panel A, CXCL1/KC in panel B, and CXCL10/IP-10 in panel C) were quantified in serum of immunized animals pre-dose, 6h and 24h post dosing, using LEGENDplex Mouse Anti-Virus Response flow-based multiplexed assay. Y-axis denotes the cytokine concentrations in pg/mL. Data shown as MeanSEM. Two-way Analysis of Variance (ANOVA) with Tukeys multiple comparison test was performed to determine statistical significance. *p<0.05, **p<0.005, ***p<0.0005, ****p<0.0001; ns - not significant. MCP-1 monocyte chemoattractant protein-1, CXCL1/KC chemokine (C-X-C motif) ligand 1/keratinocyte-derived chemokine, CXCL10/IP-10 chemokine (C-X-C motif) ligand 10/ IFN--inducible protein 10.
A Guilford County mother hopes the state Supreme Court will take the case of her teenage sons forced COVID vaccine shot. The mother and son sued the Guilford County school board and the Old North State Medical Society over the 2021 incident.
A unanimous state Court of Appeals panel ruled in March against mother Emily Happel and son Tanner Smith. Appellate judges agreed that the federal Public Readiness and Emergency Preparedness Act of 2005 protected the school board and medical society against legal action.
Happel and Smith filed a petition Friday asking the states highest court to reverse that ruling.
The pandemic that occurred from 2020-2022 caused a seismic shift in the social, medical, political, and legal landscape of not only the State of North Carolina, not only the United States, but the world as a whole, wrote lawyer David Steven Walker. How the government chose to deal with the pandemic, especially concerning the administration of vaccines that had been granted emergency use authorizations, was and is a hotly contested issue, one that is certainly of significant public interest.
This public interest is even more significant when the issue revolves around the vaccination of a minor and the allegation that neither the minor nor the minors parent consented to the administration of the vaccine, Walker added.
The case deals with the interplay between duty of the courts of North Carolina to remedy constitutional and other legal violations and a federal law that defendants purport forecloses that opportunity, Walker wrote.
The trial court and the Court of Appeals interpreted the PREP Act so broadly as to shield nearly every act, no matter how egregious, from any legal consequence, according to the petition. Further, the Court of Appeals and the trial courts decision rendered totally useless N.C. Gen. Stat. 90-21.5(a1) which prohibited the very acts committed by defendants. It is now a law of aspiration, with no consequence for its blatant violation.
The quoted state law NCGS 90-21.5(a1) says, Notwithstanding any other provision of law to the contrary, a health care provider shall obtain written consent from a parent or legal guardian prior to administering any vaccine that has been granted emergency use authorization and is not yet fully approved by the United States Food and Drug Administration to an individual under 18 years of age.
The Appeals Court issued a unanimous March 5 decision against the mother and son despite labeling the forced vaccination egregious.
Plaintiffs argue the trial court erred in determining that the PREP Act is applicable to this case and provides immunity to both Defendants, Judge April Wood wrote. Due to the sweeping breadth of the federal liability immunity provision in the PREP Act, we are constrained to disagree.
Bound by the broad scope of immunity provided by the PREP Act, we are constrained to hold it shields Defendants, under the facts of this case, from Plaintiffs claims relating to the administration of the COVID-19 vaccine, Wood added.
In August 2021, Smith was a 14-year-old Western Guilford High School football player. His family learned in a letter from the Guilford schools that Smith might have been affected by a COVID-19 cluster involving the team. He would not be allowed to return to practice until getting a COVID test.
Free testing would be provided at Northwest Guilford High School. The letter indicated ONS Medical Society would conduct the testing and consent for testing is required, Wood wrote.
Smiths stepfather drove him to the testing site and waited outside the building. The teenager was asked to fill out a form while a clinic worker tried unsuccessfully to contact his mother. Smith and his family didnt know the clinic also provided COVID-19 vaccine shots.
After failing to make contact with Tanners mother, one of the workers instructed the other worker to give it to him anyway. Tanner stated he did not want a vaccine and was only expecting a test, but one of the workers administered a Pfizer COVID-19 vaccine to him, Wood wrote.
Happel and Smith filed suit in August 2022. A trial judge dismissed the case in March 2023.
Appellate judges ruled that both the school board and medical society were covered by the federal PREP Act. A declaration from the secretary of the US Department of Health and Human Services in March 2020 offered protection related to the COVID-19 vaccine.
[W]e hold ONS Medical Society is a covered person as a program planner that administered a vaccine clinic, and individually administered vaccines to individuals. The declaration clearly provides that a program planner may be a private sector employer or community group when it carries out the described activities including administration of a covered countermeasure, Wood wrote.
The same law also applied to the Guilford school board. We are convinced by the Secretarys interpretation in the declaration that a covered person under the PREP Act includes a state or local government . . . [that] provides a facility to administer or use a Covered Countermeasure. We hold this language includes the Board, which provided a facility Northwest Guilford High School for the administration of the COVID-19 vaccines, Wood wrote.
Wisely or not, the plain language of the PREP Act includes claims of battery and violations of state constitutional rights within the scope of its immunity, and it therefore shields Defendants from liability for Plaintiffs claims, Wood added.
The Appeals Court noted that North Carolinas General Assembly amended state law in 2021 to require parental consent before a vaccine granted emergency use authorization may be administered to a minor.
Its intent is to prevent the egregious conduct alleged in the case before us, and to safeguard the constitutional rights at issue Emilys parental right to the care and control of her child, and Tanners right to individual liberty, Wood wrote. Notwithstanding, the statute remains explicitly subject to any other provision of law to the contrary under the broad provision preempting state law in the PREP Act.
The PREP Act provides only one exception for a Federal cause of action against a covered person for death or serious physical injury proximately caused by willful misconduct. Because Plaintiffs have not made any such allegations in their complaint, we are constrained to conclude the PREP Act preempts the protections provided by state law, Wood wrote.
Judges Allegra Collins and Jeff Carpenter joined Woods decision.
Chicago has seen 56 measles cases this year, accounting for over half of the cases across the country.
The Centers for Disease Control and Prevention also reports more than half of cases are in children under the age of 5.
The Chicago Department of Public Health says they are fighting the spread through testing and vaccinations particularly in the Pilsen migrant shelter where the majority of cases are emerging.
Dr. Brian Borah, medical director for vaccine-preventable diseases at the Chicago Department of Public Health, says their efforts have led 6,000 people receiving vaccinations at 75 different vaccine events since March.
I think we were able to get ahead of the virus in that way, he said. And we really have targeted most of the shelters housing these new arrivals in Chicago and we think have put a good dent in this outbreak.
CDPH has not specified how many cases are from the Pilsen migrant shelter but they have said it is not the source.
Clearly weve had a lot of cases come out of that setting, Borah said. But I think its an open question about how measles came to be in that setting Certainly the measles was in Chicago before this outbreak started. So we think that there are somehow links to one of those two cases or another case that were not sure about, but were still investigating those details.
Children under 5 are considered high risk of becoming very sick
Someone with measles typically starts showing symptoms similar to a cold such as a cough, runny nose or red eyes. A rash, which often starts at the head and moves down to the rest of the body, then signals a measles case.
Measles is one of the most contagious diseases and children under 5 are considered at high risk of becoming very sick from it, according to Borah. But he added vaccination is the key to immunity. If someone is unsure of their vaccination status, a blood test can be used.
During the visit, staff and processes are reviewed to ensure full compliance is being met according to the programs standards. Various categories of the review include all VCF providers:
Vaccinations are among the most effective tools in our public health toolbox, said Ryan Talken, Director of Joplins Health Department. Vaccines have greatly reduced diseases, and in some cases, eliminated instances of certain diseases.
The Medical Division of the Health Department manages the Vaccine For Children.
Joplin Health nurses work with businesses, schools, and other locations throughout the year to offer vaccinations in convenient locations to those seeking them. They also lead numerous vaccination clinics as parents prepare for school enrollment.
For more information about the Joplin Health Departments Vaccination for Children Program, call 417-623-6122, ext. 1289.
Due to the recent measles outbreak in Chicago, IL NorthShore Health Centers wanted to share information regarding the importance of receiving your measles vaccine. Dr. Sankaran also shares what symptoms to watch for if you are unvaccinated.
Visit https://northshorehealth.org/ to view a list of providers available at a convenient location near you providing services to four counties in Northwest Indiana.
Pre-exposure prophylaxis clinical trials of a 3-dose regimen of Verorab followed by a booster dose at 1 year in adults and children achieved an adequate immune response.1
Of those who had a booster dose at 1 year, 96.9% of vaccinated individuals maintained a protective antibody response for 10 years.1
Post-exposure phase 4 prophylaxis clinical trials showed individuals bitten by animals with rabies and treated with a 5-dose regimen of Verorab were all alive 3 years after post-exposure prophylaxis.1
Adverse reactions were moderate in intensity and most resolved within 1 to 3 days of their onset.1
READING, U.K., April 05, 2024--(BUSINESS WIRE)--Sanofi (EURONEXT: SAN and NASDAQ: SNY) has today announced the launch of Verorab (Sanofi Inactivated Rabies Vaccine) in the UK, an inactivated rabies vaccine indicated for pre-exposure and post-exposure prophylaxis of rabies in all age groups.1
This launch is based on extensive clinical data from over 13,000 individuals.1 Sanofi Inactivated Rabies Vaccine has been approved and widely used in more than 80 countries.2 It is estimated that between 41 and 70 million individuals have received the vaccine since its first licensure in May 1985, in France.2
Rabies is nearly always fatal once symptoms appear, but can be preventable with vaccination3
Each year, an estimated 59,000 people worldwide die from rabies.4 Thats one person every nine minutes of every day3, with approximately 95% of deaths occurring in Asia and Africa.3,4,5 Individuals travelling to these countries should be aware of the risk of rabies and take the appropriate precautionary measures.
Rebecca Catterick, UK and Ireland Sanofi Vaccines General Manager, said:
"Rabies is a fatal, travel-related vaccine-preventable disease. The availability of Verorab in the UK provides an effective immunisation option for those travelling to high-risk countries, as well as a treatment for post-rabies exposure."
Joanna Lowry, Specialist Travel Nurse & Educator, said:
Story continues
"I am always surprised by the number of British travellers I meet who are unaware of the risk of rabies. Increasing awareness and sharing education on preventative measures is crucial to help reduce the possibility of this devastating disease."
Rabies in the UK is extremely rare,6 and the last case of classical rabies acquired in the UK occurred more than a century ago.6
Rabies is primarily transmitted by the bite, scratch, or lick of a rabid animal, 99% of which are by dogs, but can also be other wildlife, such as foxes or bats.6
About Verorab (Sanofi Inactivated Rabies Vaccine)
Sanofi Inactivated Rabies Vaccine is indicated for pre-exposure and post-exposure prophylaxis of rabies in all age groups and should be given according to official recommendations.1 It can be used for both primary and booster vaccination and pre-exposure prophylaxis.1 Post-exposure prophylaxis should be initiated as soon as possible after suspected exposure to rabies, and must be performed before administration of vaccine or rabies immunoglobulins, when they are indicated.1 Pre-exposure vaccination consists of intramuscular (IM) injections of Sanofi Inactivated Rabies Vaccine.1 Post-exposure prophylaxis can be administered via IM or intradermal (ID) routes.1
Most commonly observed side effects include pain at the injection site, a general feeling of discomfort or being unwell (malaise), and headache.1 Injection site reactions (pain, erythema and swelling) were more common after an ID injection than an IM injection.1 Pain was the most common injection site reaction for both administration routes.1
Sanofi Inactivated Rabies Vaccine is available as a lyophilised powder and a solvent (sodium chloride) for suspension for injection, containing inactivated rabies virus, and is available with or without attached needles.1
About Sanofi
We are an innovative global healthcare company, driven by one purpose: we chase the miracles of science to improve peoples lives. Our team, across some 100 countries, is dedicated to transforming the practice of medicine by working to turn the impossible into the possible. We provide potentially life-changing treatment options and potentially life-saving vaccine protection to millions of people globally, while putting sustainability and social responsibility at the centre of our ambitions. Sanofi is listed on EURONEXT: SAN and NASDAQ: SNY.
References
1 Verorab SmpC. November 2023. 2 Sanofi Vaccines. Data on file. 3 WHO. Zero by 30: the global strategic plan to end human deaths from dog-mediated rabies by 2030. Available at: https://iris.who.int/bitstream/handle/10665/272756/9789241513838-eng.pdf?sequence=1. Accessed March 2024. 4 WHO. Rabies vaccines: WHO position paper April 2018. Wkly Epidemiol Rec. 2018;93(16):201-20. 5 WHO. Rabies key facts. September 2023. Available at: https://www.who.int/news-room/fact-sheets/detail/rabies. Accessed March 2024. 6 Gov.UK. Rabies: epidemiology, transmission and prevention. Available at: https://www.gov.uk/guidance/rabies-epidemiology-transmission-and-prevention#:~:text=Human%20rabies%20in%20the%20UK,-Human%20rabies%20is&text=Cases%20occurring%20since%20then%20have,from%20the%20Philippines%20and%20Nigeria. Accessed March 2024.
View source version on businesswire.com: https://www.businesswire.com/news/home/20240404662602/en/
Contacts
Sanaz Ayoughi, UK & Ireland Sanofi Vaccines Communications Lead |+44 (0) 7753 717 109 sanaz.ayoughi@sanofi.com
