(Precision Vaccinations News)
Costa Rica's Ministry of Health (MOH) and the Caja Costarricense del Seguro Socialhave begun investigating a potential outbreak of Bordetella pertussis (whooping cough) in the district of Tibas, located north ofSan Jose.
This is the same area in Costa Rica where the MOH has reported chikungunya, dengue, malaria, and Zika cases in 2024.
As of April 11, 2024, given the contagious nature of whooping cough and its severity in children and unvaccinated populations, the U.S. Embassy urges heightened awareness and vaccination verification for U.S. citizens in Costa Rica.
Before visiting Costa Rica in April 2024, the U.S. CDC advises international travelersto speak with a travel vaccine expert regarding their options one month ahead of departure.
In the Boston, Massachusetts, area, travel vaccination services are offered at Destination HealthTravel Clinic.
COVID Vaccination during Pregnancy Protects Newborn Babies
Studies show that vaccination against COVID during pregnancy provides a powerful safeguard for vulnerable infants too young to receive the vaccine on their own
By Shannon Hall
Stock photo. For illustrative purposes only.
ArtistGNDphotography/Getty Images
When Emily Kara was 34 weeks pregnant, she received an additional COVID vaccine. She did not technically qualify for one. She had received her latest dose merely five months earlier, and her midwife even advised against another shot. But Kara (who asked to go by her middle name out of concern for her privacy) was determined. She had read multiple studies that strongly suggested a maternal COVID vaccine would pass along antibodies to her baby girl and protect her after she was born, when she was vulnerable to SARS-CoV-2 (the virus that causes COVID) and too young to receive the vaccine herself.
So Kara received an extra shot. And she is incredibly thankful that she did. It gives me peace of mind, says Kara, whose baby is now nine months old and has not tested positive for COVID.
The first wave of COVID vaccine trials that began in 2020 excluded pregnant peopleleaving expectant parents in the dark as to the vaccines safety for themselves and their child. But now that millions of pregnant people have received the vaccines, the data are solid. Not only do they show that the vaccines are safe and effective during pregnancy, but a growing consensus is also emerging that vaccinating a pregnant person against COVID can protect their newborn at a time when their little ones immune system is not mature enough to mount its own defense. Some studies even suggest that the protection lasts until roughly six months of age, when infants are old enough to receive their own vaccine.
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The science is relatively simple: when a COVID vaccine is given during pregnancy, the parents immune system develops antibodies against a protein in SARS-CoV-2 that then cross the placenta to the fetus and thus protect the newborn. This is why pregnant people have long been advised to receive the flu shot and the Tdap (tetanus, diphtheria and pertussis) vaccine. And one vaccinethe respiratory syncytial virus (RSV) vaccine approved last yearwas even developed specifically to be given during pregnancy to protect the baby after birth. That is something that we really ought to be leveraging for COVID as well, says David Kimberlin, a pediatric infectious disease specialist at the University of Alabama at Birmingham. I think the data are clear.
A study published in March in Pediatrics from the National Institute of Allergy and Infectious Diseases (NIAID) found that mothers who received an mRNA-based COVID vaccine during pregnancy protected their infant against symptomatic COVID infection for at least six months after birth. Last fall the U.S. Centers for Disease Control and Prevention similarly noted that infants born to women who had received a COVID vaccinebe it the primary series or a boosterat any point during pregnancy had a decreased risk of COVID hospitalization compared with infants who were born to women who had never received a COVID vaccine. And a study published in Nature Medicine in March 2023 found that newborns born to mothers who were vaccinated with a third (booster) dose were half as likely to be hospitalized for COVID as newborns born to mothers who had received the primary series and were eligible for a third dose during pregnancy but had not received it.
This protection is great news given COVIDs risk to newborn babies. One of the facts that gets lost in the general public is that in the pediatric population, COVID is most severe among young infants, resulting in the highest rates of hospitalization and death in this young age group, says Cristina Cardemil of the NIAID, who led the Pediatrics investigation. The hospitalization rate in babies under six months increased during the Omicron period and rivals that of adults aged 65-74. Not only have these infants never encountered these infectious diseases but they also have small airways and become dehydrated easily. Theyre doubly at risk for being vulnerable to a number of infectious diseases, Cardemil says.
Now expectant parents have a tool to shield their baby. Multiple studies show similar findings, and many suggest that a COVID booster during the second or third trimester confers the best protection. The Nature Medicine study authors write: We anticipate that future guidelines will adopt recommendations for routine COVID booster vaccination during the third trimester, aiming to reduce early infant morbidity, similar to recommendations for pertussis and influenza prevention.
And yet that is not the case. The CDC currently recommends that everyone, pregnant people included, receive the most recent version of the COVID vaccine, but it does not recommend an additional booster to ensure vaccination during pregnancy or point toward a specific administration time. For example, a pregnant person could receive a COVID vaccine in the fall before conceiving and deliver a baby before the next fall vaccine is releasedthus missing out on the benefits that an extra vaccine dose confers. The World Health Organization does recommend a single additional dose of the COVID vaccine during pregnancy, but this guideline seems to be the exception. In January, for example, Canadas National Advisory Committee on Immunization provided guidance on who should get an additional spring booster, and pregnant people were not mentioned. The same was true for the U.K.s spring booster campaign. (Guidelines from both countries note that the vaccine is safe and effective during pregnancy.)
The issue, experts say, is COVID fatigue. Governing agencies must make recommendations based on what is actually feasible, and an extra booster might be a hard sell when so few pregnant people are up to date on their COVID vaccine in the first place. In the U.S., for example, a mere 13 percent of pregnant people aged 18 to 49 have received the updated 20232024 COVID booster. People are very lackadaisical about it, says Laura Riley, chair of obstetrics and gynecology at Weill Cornell Medicine in New York City. And Im in a place where people get vaccinated. So the CDC has streamlined the most important message: vaccination protects against disease.
In response to a request for comment, a spokesperson from the CDC said: Available data show the vaccines for all eligible peopleincluding pregnant peoplecontinue to be strongly protective against severe illness and death. For that reason, the agency recommends that pregnant people stay up to date on their vaccines, but it will continue to review available evidence on whether additional or differently timed doses might be needed.
Yet many experts argue that the recommendation does a disservice to pregnant people, who are at heightened risk from the disease, and their newborn. The politicization of vaccines has led to this vaccine not being utilized as much as it should be, says Sallie Permar, chair of pediatrics at Weill Cornell Medicine and pediatrician in chief at NewYork-Presbyterian Komansky Childrens Hospital. She argues that the COVID vaccine clearly falls into the same category as the flu and Tdap vaccines, whose safety records and the benefits to both mom and baby have just been universally awesome.
Kimberlin agrees and is hopeful that the tides will soon shift toward stronger recommendations and a higher vaccine uptake during pregnancy. This is a very easy way to keep your baby safe, he says. And it absolutely should be recommended vigorously.
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Catherine J. Wu has been a pioneer in a promising approach to fight cancer: a vaccine that targets the specific immunogenic peptides generated by the distinct tumor mutations of any individual cancer. Honored in February with the $1 million Sjberg Prize, given for cancer research, Wu, a professor of medicine at Harvard Medical School and Lavine Family Chair for Preventative Cancer Therapies at the Dana-Farber Cancer Institute, spoke with the Gazette about the technology, its promise, and expectations that patients might see it in the near future.
What is a cancer vaccine?
A cancer vaccine aims to vaccinate the individual against immune determinants present in cancer cells to mount an immune response and hopefully eliminate those cancer cells. In general, cancer vaccines are therapeutic vaccines, meaning that they are treating an existing cancer, as opposed to a prophylactic vaccine, which is what we typically imagine when we think about vaccines against infectious pathogens. So, a major goal of a cancer vaccine is to drive the generation and expansion of an army of T cells that specifically recognizes tumor cells and to carry a program to eradicate that cancer. The concept of cancer vaccines has been around for decades, but until only recently, its clinical development has been quite a rollercoaster.
A major goal of a cancer vaccine is to drive the generation and expansion of an army of T cells that specifically recognizes tumor cells and to carry a program to eradicate that cancer.
Youre talking about how the vaccines get around a hurdle in convincing our immune systems to attack cancer cells: The immune system is designed to attack things that are foreign to the body, whereas cancer cells though harmful come out of our own tissues. The immune system doesnt attack because it recognizes tumors as us. Is that right?
Exactly, this is a major challenge for cancer vaccines. Our innovation is that we were among the first to identify tumor-specific peptides that are recognized by the immune system so-called antigens through genomic approaches. These neoantigens originate from cancer mutations. Since neoantigens have exquisite restriction of their expression to tumor cells, these would be optimal cancer antigens to go after, setting up the possibility of specific targeting of the cancer cell and not normal tissue. However, a long-existing problem was always the understanding that these neoantigens would differ from individual to individual and thus the conundrum of how one could feasibly go about identifying them on a person-by-person basis.
How did sequencing technology make the difference?
The availability of next-generation sequencing over the past decade, in which time and cost advantages for the DNA and RNA sequencing of cancer samples has been achieved such that weve been able to sequence thousands upon thousands of cancers. That has given us the stark realization of the vast molecular heterogeneity from tumor to tumor, even among patients with the same type of cancer. This fact really brings home the idea that a one-size-fits-all approach to cancer treatment or immunotherapy has its limitations. The ability to readily scan cancer genomes through such technology has made it possible to directly find the mutational profile of each cancer, and then to identify those mutations that have the potential to generate neoantigens.
Once we realized that it was possible to systematically identify neoantigens from cancer sequences, we began to realize that perhaps we could generate a personalized cancer vaccine: that from the mutation profile of any patient, we could design peptides that encompass those mutations that were predicted to be immunogenic. We then devised a manufacture strategy to combine up to 20 of those peptides into a vaccine that we could administer to patients as a series of skin injections that we could give to patents over the course of several weeks.
Im sure readers have heard and read a lot about cancer immunotherapy. How are vaccines related?
There are many different types of immunotherapy and this fact reflects the many, many different functions and roles that T cells and other immune cells can play. Each immunotherapeutic modality leverages a different subset of those functionalities: A CAR-T cell or an immune checkpoint blockade are different from what a vaccine might do. What they have in common, however, is that they are each stimulating immunity. A vaccine is trying to either generate new immune responses in an antigen-specific way that didnt exist before or they can amplify small pre-existing responses to become bigger. So, a vaccine has the potential to cast a wide immunoprotective net that can endure over time.
I hope that sometime in the not-too-distant future our patients can go to a clinic and say, Order me up a vaccine personalized for my cancer, and well be able to administer it on site.
In your first study that came out in Nature in 2017, you treated six melanoma patients. Do we know how theyre doing today?
I do know that three to four years after receiving the vaccine, all patients were still alive. We reported this result in 2021. Remarkably, two study patients who had very advanced cancer stage IV disease saw their cancer recur soon after vaccination. However, they both also got the immune checkpoint blockade and within 12 weeks all detectable tumor melted away. Its been now about six or seven years since then and these patients are off therapy and doing really well. Thats a huge success story and speaks to the strong positive synergy between vaccines and immune checkpoint blockade therapy.
What other types of cancer have been treated with these vaccines?
At Dana-Farber, we have treated patients in ongoing trials who have glioblastoma, kidney cancer, ovarian cancer, melanoma, and chronic lymphocytic leukemia. Separately, I also co-founded a company called Neon Therapeutics several years ago that conducted a larger study that treated patients with melanoma, lung, and bladder cancer.
Are these cancers chosen for any particular reason?
Cancer vaccines are cross-cutting as a treatment modality and can be tested in virtually any setting and in any cancer. Our selection has to do with the research questions that we are pursuing and I truly have had the privilege of working with so many extraordinary clinical investigators.
Are these all small, like the initial melanoma trial?
Yes, at Dana-Farber, our academic trials continue to be small, Phase 1 studies, of 10 to 30 patients. Our focus has been to take deep dives into the study of every single patient to understand what our interventions are doing immunologically.
Whats exciting is that there also now is a series of industry-sponsored studies my research group is not involved in them that are ongoing nationwide, even worldwide, that, hopefully within the next two or three years, will give us a population-level view of the impact of such personal cancer vaccines. Last fall, the first randomized, Phase 2 trial was reported out that demonstrated in melanoma the benefits of immune checkpoint blockade with a personalized cancer vaccine compared to immune checkpoint alone. I think were at an inflection point where the conceptual advantage of targeting many, many personal neoantigens simultaneously is undergoing rigorous testing. Such a personalized, multitarget approach is of conceptual importance because of the tremendous heterogeneity of tumor cell populations.
Even within one persons body?
Yes, exactly, and that is why a multipronged attack against cancer is favorable.
How big a hurdle is the fact that because these are so personalized, even with a trial of 10 or 30 people, you have to find new neoantigens for each person in the trial? Its not like youre trying the same drug on all 30.
It has its challenges. But with teams like ours at DFCI we are a collection of immunologists, clinical investigators, computational biologists, surgeons, and medical oncologists we are able to design these vaccines together in real time. It certainly takes a village, and I am so grateful to be part of that village. Given the challenge of coordinating the many parts of vaccine manufacture, this is an instance where partnering with industry is helpful, because they have the resources to develop processes at scale, streamlining costs, time, and labor. All of this is actively being figured out.
How far away are these vaccines from getting into the clinic?
Sooner than we think, because of academic innovations and industry-level efforts. Many large trials are ongoing now and I do think that theyll read out within two years. So, I hope that sometime in the not-too-distant future our patients can go to a clinic and say, Order me up a vaccine personalized for my cancer, and well be able to administer it on site.
Key Takeaways
Moderna (MRNA) shares jumped Tuesday after the biotech firm reported positive results from a small trial involving those with head and neck cancers treated with its experimental individualized MRNA cancer vaccine combined with Mercks (MRK) blockbuster drug Keytruda.
The study involved 22 patients with human papillomavirus negative (HPV-) head and neck squamous cell carcinoma who received Modernas mRNA-4157 injection along with Keytruda.
The company reported the drug cocktail produced preliminary positive clinical responses and disease control, including two complete responses. It added that along with boosting the immune response, the treatment was well tolerated.
The data were presented at the American Association for Cancer Research annual meeting in San Diego, Calif. yesterday. In its report, Moderna explained that a randomized assessment of the mRNA-4157-Keytruda combinations effect in the advanced disease setting may be warranted.
In December, Moderna and Merck announced they were initiating a Phase 3 trial of the two drugs to treat certain forms of lung cancer.
Moderna stock gained 6.2% to close at $111.60, making it the biggest gainer on the S&P 500 Tuesday. Merck shares ended 0.1% higher at $126.71.
Most Republican voters support childhood vaccine mandates, yet may be discouraged from publicly expressing these views, a new study suggests.
To determine the source of this disconnect, researchers conducted a survey that revealed differences between Republican voters who support childhood vaccine mandates and those who do not.
According to the study, most Republicans surveyed supported immunization requirements for children and held favorable attitudes toward vaccine safety, while those who said they opposed vaccine mandates did not acknowledge this support exists and expressed a greater willingness to share their vaccine views to others.
In contrast, the Republicans who supported vaccine mandates were largely aware that their views were in the majority, but tended to be less outspoken.
This phenomenon, called the false consensus effect, describes a misperception by people about how widespread their views are and a belief that their opinions are shared by others when they are not.
These results suggest that conservative supporters of childhood vaccination are not discouraged from speaking out because they assume that they are in the minority, but because external information environments, like social media, are sometimes dominated by minority views, said Graham Dixon, lead author of the study and an associate professor of communication at The Ohio State University.
Those in the majority may simply sit out of the conversation because they see online environments as being dominated by extreme views and dont want to engage in uncivil discourse, said Dixon. Whats significant is that those in the majority may self-silence even when they are aware of their majority status.
The study was recently published in the journal Human Communication Research.
The work is especially notable because it corroborates recent research showing that much of social media content is driven by a minority of users who express more opinionated and politicized views than the typical user, said Dixon.
Social media has become the new public square, so its concerning that the overrepresentation of atypical and sometimes extreme views may discourage people from participating in the conversation, he said.
This overrepresentation, notes the study, can discourage those in the majority from speaking out because they fear that they may experience social conflict from doing so.
For example, when participants who supported immunization requirements were frequently exposed to anti-vaccine content on social media, they were more likely to believe that they would encounter conflict if they publicly voiced their support for vaccines.
This is likely a larger consequence of the online social environment, as social media can be used to amplify misleading information that represents the views of only a small subset of the population, said Dixon. In this case, such large-scale self-censorship could play a role in hindering public mobilization of important public health policies.
Researchers also found that the studys results reveal more about majority misconceptions about a number of other issues, including how much support there is for climate change mitigation policies. For society to combat these issues, Dixon suggests that helping individuals build more self-confidence when engaging in online discourse and encouraging them to gain greater media literacy to navigate societys fluctuating information environment could be better tools for overcoming self-silencing.
We need to figure out ways of motivating people to engage in online discourse and to have the self-confidence necessary to be able to present their views, he said. Instead of telling them that their views are in the majority, efforts should be made to empower peoples self-confidence to participate in online discourse in civil and constructive ways.
Other Ohio State co-authors include Blue Lerner and Samuel Bashian.
Ways to bring up vaccinations with family and friends that maintains relationships and sets healthy boundaries.
Having conversations about sensitive topics can be difficult for anyone, especially something as personal as our health. It can be difficult to bring up topics such as health and vaccines with the people we love, set boundaries where needed, and reconcile the need for social connections to stay healthy overall.
The World Health Organization (WHO) recommends five steps for discussing vaccines with loved ones:
In a recent series of webinars, Dr. Ida Rubino, Katie Stanulis, and John Novello sat down with MSU Extensions Michigan Vaccine Project to discuss how we can gather safely and talk about sensitive topics with the ones we care about.
One question that often comes up is, Is it okay to ask family and friends if theyre vaccinated, and if so, how do I do that politely?
John Novello, a licensed clinical social worker with the State of Michigan and Director of MSUs Employee Assistance Program, explained that the simple answer is yes, its okay. You really want to start with yourself getting some clarity, and actually thinking about what you are okay with and what youre not okay with before you even get to a place where youre going somewhere. Think about things like are you going to be comfortable being around people that are not vaccinated? How many people are you comfortable being around? What kind of space does that look like? And then the most important thing is to have a conversation with those you will be around. The goal of the conversation isnt to try to convince other people or talk them into being like you or thinking like you. The goal is simply to state where youre at and get information so that you can all make good choices about what makes the most sense in terms of gathering.
Novello also says that its important to discuss new social norms with family and friends before gathering. Set up your gatherings and say something like, hey, Im uncomfortable going to places when people are having flu/cold/COVID symptoms, so as a group, can we agree that if somebody is having symptoms that they let us know beforehand so everybody has full information and can decide if theyre comfortable still meeting or not. Youre creating a culture of expectation or culture of open discussion about this which can make everyone involved feel more comfortable with meeting together.
When discussing vaccines with her patients in the clinical setting, Family Physician Dr. Rubino says she aims to have conversations, based on shared decision-making, but at the same time offering resources that are reputable. In social settings, Dr. Rubino advises being honest and advocating for those you love. She says, In my own family, there are people who have COPD and currently going through chemotherapy, so for them being exposed to something is risky. I think its very appropriate to say, By the way, have you had any vaccines recently? We all love this person. We all love everyone whos gathering, so if you dont mind, are you feeling OK? Have you considered getting the vaccine? Im really just trying to protect this family member.
I think part of vaccine hesitancy is that this generation has not seen vaccine-preventable diseases because many have been eradicated or nearly eradicated. So, I think we need to really refer people to reputable sources to read about vaccines. We need to be educated as medical people about the schedule and the changes and the efficacy of these vaccines. And it really is one of the best forms of prevention that we have.
Dr. Rubino also emphasizes the need to stay connected, at the same time being mindful of those around you. I think its important that we still gather. Stay at home if youre sick; always wash your hands. If youre going to shake somebodys hand, wash your hands before you eat. Be aware of how germs are transferred. Get enough sleep, drink enough fluids, and eat healthy nutrition. And of course, get vaccinated.
The big takeaway? Be courteous. If you dont feel well, dont go to a gathering, and meet another time when youre feeling better.
Watch the webinars with Dr. Rubino, Katie Stanulis, and Jonathon Novello.
If you need help finding a doctor, try searching for primary care physicians in your area that are highly recommended, search your insurance providers website for doctors in your network, or ask for recommendations from friends and neighbors. There are also search engines that can help you narrow your search based on region and specialty needed.
To find a vaccine, check with your primary care physician, local health departments, pharmacies, and clinics. You can also visit https://www.vaccines.gov/ to locate a vaccine clinic near you.
If you would like to learn more about vaccines, check out Michigan State University ExtensionsMichigan Vaccine Project to find links to event schedules, podcasts, publications, webinars, and videos relating to vaccine education.
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Pictured: Gloved hands amid a collage of cancer treatments/Taylor Tieden for BioSpace
Parsing key trends from 7,200 abstracts on cancer-related research can be challengingtake it from someone whos spent the past week trying to do it! But pretty quickly, a few key themes became apparent at the American Association for Cancer Researchs annual meeting.
First and foremost, the programs presented are tackling difficult cancers with a high unmet need and a dire prognosis. Some of the presentations last weekend involved drug candidates targeting pancreatic cancer, for example. In 2023, the five-year survival rate for pancreatic cancer was just 12%, according to the American Cancer Society.
Two presentationsone on Bristol Myers Squibbs blockbuster immunotherapy Opdivo, the other on a messenger RNA vaccine in development by BioNTech and Genentechshowed promising signals. Opdivos trial, the first reported of a PD1 inhibitor in neoadjuvant pancreatic cancer, indicated that the drug may improve outcomes, while BioNTech and Genentechs vaccine continued to show potential in a particularly difficult-to-treat form of the disease.
This announcement also dovetailed with another prominent theme at AACR: the resurgence of cancer vaccines, which are also making inroads in advanced liver cancer, head and neck cancer, non-small cell lung cancer and glioblastoma.
Glioblastoma is a particularly aggressive form of brain cancer that carries a 5-year survival rate of just 10%; patients typically survive between 15 and 18 months after being diagnosed. A Phase I study of Diakonos Oncologys dendritic cell vaccine showed substantially increased survival in glioblastoma patients; 88% of patients remained alive a year after treatment, compared to a historical 53% of those on standard regimens.
Other platforms and approaches also appear to be breaking through against difficult-to-treat cancers, though many of the results presented at AACR are still early stage. As anticipated, antibody-drug conjugates (ADCs) were a focus, with Vincerx Pharma presenting Phase I data in metastatic tumors and Merck and Kelun-Biotech reporting a potential survival benefit from their TROP2-directed ADC in gastric cancer.
Several other modalities were also on display at AACR. Phase I data from Menlo Park, Calif.based Synthekine, for example, showed that its / biased interleukin-2 (IL-2) partial agonist, STK-012, has thus far avoided the toxicities associated with IL-2 therapies while also demonstrating a favorable efficacy profile in advanced solid tumors. And TILT Biotherapeutics reported that TILT-123, an oncolytic adenovirus armed with tumor necrosis factor alpha and IL-2, demonstrated signs of efficacy when combined with Mercks Keytruda in a Phase I trial in patients with platinum-resistant and refractory ovarian cancer.
Another therapy that drew attention at the meeting was AstraZenecas next-generation poly-ADP ribose polymerase 1 (PARP1) selective inhibitor, which experts are hopeful can negate some of the toxicities caused by drugs that inhibit both PARP1 and PARP2. Timothy Yap, vice president and head of clinical development in the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center, noted in his presentation of the positive Phase I/II trial data that there is a great opportunity to combine a selective PARP1 inhibitor with other therapies.
This was a point also made by David Weinstock, vice president of discovery oncology at Merck, who in March told BioSpacethat we are moving toward a future where we have enough medications that each work individually and have minimal side effects so that we can create even larger combinations, which offer the most benefit to people.
As a science journalist, its easy to get bogged down in the data, the results and biggest trends (ADCs for all!) and forget the human face of cancer. As a human being, its easy to get depressed by improvements that might seem incremental, but an additional six months can mean another birthday, another anniversary or the birth of another grandchild.
Elevation Oncology CSO David Dornan told me that solid cancers are almost equally as hard and different in their own right. But progress is being made. In 2023, the five-year survival rate for pancreatic cancer increased by one percentage point from the previous year, marking the second year in a row survival has increased. Overall, the cancer death rate in the U.S. has declined by 33% since 1991. I, for one, am looking forward to reading about the next advances at the American Society of Clinical Oncologys annual meeting in June.
Heather McKenzie is a senior editor at BioSpace. You can reach her atheather.mckenzie@biospace.com. Also follow her onLinkedIn.
Study cohort
A total of 106 individuals were included in this study. 87 were recruited by the occupational healthcare department of the University Hospital Bonn and 19 by the Emergency Medicine department of the University Gttingen in Germany. The first contact was established by telephone after which a written invitation and a consent form were sent to each participant. Individuals were divided into three groups according to their histories of exposure to SARS-CoV-2 antigens: individuals who had received three mRNA (encoding wild-type spike protein) vaccine doses and subsequently recovered from an omicron breakthrough infection (Vacc+O-Inf, n=37), individuals who received three mRNA (encoding wild-type spike protein) vaccine doses and were not infected with SARS-CoV-2 (Vacc, n=41), and individuals that did not get vaccinated but were infected with omicron (O-Inf, n=28). Age or sex was not among the selection criteria. Following gender distribution was observed between the groups: 65% females and 35% males for the Vacc+O-Inf group, 66% females and 34% males for the Vacc group, 50% females and 50% males for the O-Inf group, and 57% females and 43% males for the subgroup of 7 O-Inf individuals with available PBMC samples. No significant differences in age distribution were observed between the groups (mean yearsSD for O-Inf, Vacc+O-Inf, Vacc groups and a subgroup of 7 O-Inf individuals with available PBMC samples respectively: 5021, 4015, 4714, 4413). SARS-CoV-2 infections were confirmed by RT-PCR. During the period of sample collection, the prevalence of omicron variants was >99% as assessed by sentinel sequencing. Detailed information on the vaccination, infection, and sampling time points as well as demographic information is provided in supplemental table1. All individuals with omicron SARS-CoV-2 infection did not have previously confirmed SARS-CoV-2 infection. For the Vacc group only individuals without confirmed SARS-CoV-2 infection, and negative nucleocapsid ELISA results were included. Vaccinations of individuals included in this study were performed at the occupational healthcare department of the University Hospital Bonn.
The study was approved by the Ethics Committee of the Medical Faculty of the University of Bonn (ethics approval number 125/21) and the Ethics Committee of University Medical Center Goettingen (ethics approval number 21/06/22). All participants provided written informed consent. No compensation was provided for the participants.
Study participants provided peripheral blood specimens that were centrifuged for 10min at 600g to collect plasma. EDTA plasma was stored until analysis at 80C. PBMC were isolated by density gradient centrifugation using SepMate (Stemcell, 85450) tubes with density gradient medium (Pancoll, PAN-Biotech, P04-60500). The blood was diluted with PBS containing 2% FCS, carefully layered on top of the density gradient medium, and centrifuged at 1200g for 10min. The top layer containing the PBMCs was poured off and washed twice with PBS containing 2% FCS. Washed PBMC were resuspended in FCS containing 10% DMSO and frozen at 80C overnight. For long-term storage, PBMC samples were transferred to liquid nitrogen.
An in-house quantitative ELISA was used for the determination of omicron-SARS-CoV-2-RBD-specific IgG. First, microtiter plates with high binding capacity were coated with 100l of coating buffer (carbonate-bicarbonate buffer, pH=9.6) containing 1g/ml of recombinant omicron SARS-CoV-2 RBD protein (SARS-CoV-2 Spike RBD, His Tag (B.1.1.529/Omicron), Acro Biosystems, SPD-C82E8) and incubated overnight at 4C. After washing with wash buffer (PBS with 0.05% (v/v) Tween-20) plates were blocked (PBS containing 1% (w/v) BSA) to prevent unspecific binding. Cryopreserved EDTA plasma samples were thawed and diluted 400-fold in the blocking buffer. After blocking, plates were washed, incubated with plasma samples, standard dilutions, and negative control (Human IgG Isotype Control, Invitrogen, 12-000-C, 100ng/ml), washed again, and incubated with 100l of HRP-conjugated anti-IgG antibody (Goat anti-Human IgG (Heavy chain) Secondary Antibody, HRP, Invitrogen, A18805) diluted 8000-fold in wash buffer. All incubation steps were performed at 37C for 1hour. Finally, plates were washed and 100l of the substrate solution was added (TMB Chromogen Solution, Life technologies, 002023). The substrate conversion took place at room temperature for 5min until the addition of 50l of 0.2M H2SO4. The optical density at 450nm (OD450) was measured using Synergy 2 Multimode Plate Reader (BioTek). The background-subtracted OD450 readings were interpolated to the standard dilution curve. The positivity cutoff was determined as the mean plus two standard deviations of plasma samples from healthy individuals collected before the COVID-19 outbreak.
An in-house competitive ELISA was used for the determination of IgG specific for the omicron but not wild-type SARS-CoV-2 RBD. Microtiter plates with high binding capacity were coated with 100l of coating buffer (carbonate-bicarbonate buffer, pH=9.6) containing 1g/ml of recombinant omicron SARS-CoV-2 RBD protein (SARS-CoV-2 Spike RBD, His Tag (B.1.1.529/Omicron), Acro Biosystems, SPD-C82E8) or 1g/ml of BSA and incubated overnight at 4C. After washing with wash buffer (PBS with 0.05% (v/v) Tween-20) plates were blocked (PBS containing 1% (w/v) BSA) to prevent unspecific binding. Cryopreserved EDTA plasma samples were thawed and diluted in the blocking buffer. The plasma dilutions were calculated based on the previous measurement of omicron-SARS-CoV-2-RBD-specific IgG to achieve the OD450 of 2. Diluted plasma was then incubated with serial dilutions of wild-type RBD protein (SARS-CoV-2 (COVID-19) S protein RBD, His Tag, Acro Biosystems, SPD-C52H1). A total of 8 dilutions between 1g/ml and 0,002g/ml were measured for each sample. No further technical replicates were performed. Blocked RBD-coated plates were washed, incubated with plasma samples, standard dilutions and negative control (Human IgG Isotype Control, Invitrogen, 12-000-C, 100ng/ml), washed again, and incubated with 100l of HRP-conjugated anti-IgG antibody (Goat anti-Human IgG (Heavy chain) Secondary Antibody, HRP, Invitrogen, A18805) diluted 8000-fold in wash buffer. BSA-coated plates were incubated with three replicates of diluted plasma samples without wild-type RBD and treated equally. All incubation steps were performed at 37C for 1hour. Finally, plates were washed and 100l of the substrate solution was added (TMB Chromogen Solution, Life technologies, 002023). The substrate conversion took place at room temperature for 5min until the addition of 50l of 0.2M H2SO4. The optical density at 450nm was measured using Synergy 2 Multimode Plate Reader (BioTek). The background-subtracted OD450 readings were interpolated to the standard dilution curve. For each plasma sample incubated with wild-type RBD dilution series a scatter plot was generated and a sigmoidal curve was fitted to determine the top (representing the signal from total omicron-RBD-specific IgG) and bottom (representing the signal from omicron-not-wild-type-RBD-specific IgG) plateaus of the curve. GraphPad Prism software version 9.4.1. (681) was used for this purpose. The background signal of the BSA control was then subtracted from the bottom and top plateaus after which the two values were divided to obtain the proportion of omicron-not-wild-type-RBD-specific IgG relative to the total omicron-RBD-specific IgG. This fraction was multiplied with the corresponding quantitative ELISA measurement to obtain the level of omicron-not-wild-type-RBD-specific IgG in plasma.
The plasma neutralization capacity was determined by a plaque reduction neutralization assay. Therefore, plasma was heat-inactivated for 30min at 56C and serially two-fold diluted in OptiPRO SFM (Gibco, 12309-019) cell culture medium. A total of 10 dilutions between 4-fold and 32768-fold were measured for each sample depending on the neutralization capacity of a specimen. No further technical replicates were performed. Each plasma dilution was combined with 80 plaque-forming units of omicron SARS-CoV-2 (B.1.1.529 in OptiPRO SFM (Gibco, 12309-019) serum-free cell culture medium, incubated for 1h at 37C, and added to Vero E6 cells (ATCC, CRL-1586). The cells were seeded in 24-well plates at a density of 1.25105 cells/well 24h earlier. Following 1h incubation at 37C, the inoculum was removed and cells were overlaid with a 1:1 mixture of 1.5% (w/v) carboxymethylcellulose in 2xMEM supplemented with 4% FCS. After incubation at 37C for four days, the overlay was removed and the cells were fixed using a 6% formaldehyde solution. Fixed cells were stained with 1% crystal violet solution revealing the formation of plaques. The number of plaques was plotted against the plasma dilutions, and the half-maximal inhibitory concentration (IC50) was determined using GraphPad Prism software version 9.4.1. (681).
To measure the proportion of neutralizing antibodies that recognize mutated regions of the omicron SARS-CoV-2 surface proteins we developed a competitive plaque reduction neutralization assay. First, plasma was heat-inactivated for 30min at 56C and diluted in OptiPRO SFM (Gibco, 12309-019) serum-free cell culture medium. The plasma dilutions were calculated based on the previous measurement of plasma neutralization capacity against the omicron-SARS-CoV-2 to achieve the 80% neutralization effect. Diluted plasma was then incubated with 12 serial 2-fold dilutions of wild-type SARS-CoV-2 surface proteins, spike (Acro Biosystems, SPN-C52H7), membrane (RayBiotech, YP_009724393) and envelope (Acro Biosystems, ENN-C5128) starting with 10ug/ml and incubated overnight at 4C. Plasma sample dilutions, standard dilutions, and negative controls (media without plasma) were combined with 80 plaque-forming units of omicron SARS-CoV-2 (B.1.1.529) in OptiPRO SFM (Gibco, 12309-019) serum-free cell culture medium, incubated for 1h at 37C, and added to Vero E6 cells (ATCC, CRL-1586). The cells were seeded in 24-well plates at a density of 1.25105 cells/well 24h earlier. Following 1h incubation at 37C, the inoculum was removed and cells were overlaid with a 1:1 mixture of 1.5% (w/v) carboxymethylcellulose in 2xMEM supplemented with 4% FCS. After incubation at 37C for four days, the overlay was removed and the cells were fixed using a 6% formaldehyde solution. Fixed cells were stained with 1% crystal violet solution revealing the formation of plaques. The number of plaques was plotted against the concentration of the surface proteins and a sigmoidal curve was interpolated using GraphPad Prism software version 9.4.1. (681). The top (representing the signal from omicron-not-wild-type-neutralizing antibodies) and bottom (representing the signal from total omicron-neutralizing antibodies) plateaus of each curve were interpolated from a standard curve and divided to obtain the proportion of omicron-not-wild-type-neutralizing antibodies relative to the total omicron-neutralizing antibodies. This fraction was then multiplied with the corresponding quantitative IC50 to obtain the level of omicron-not-wild-type-neutralizing antibodies in plasma.
Cryopreserved PBMC samples were thawed and rested overnight at 37C. The next morning, B cells were isolated immunomagnetically (REAlease CD19 MicroBead Kit, human, Miltenyi Biotec, 130-117-034) following the manufacturers instructions. Briefly, cells were resuspended in the recommended isolation buffer, labeled with anti-CD19 antibodies coupled to magnetic beads, and passed through a magnetic column. B cell-depleted flow-through was collected for the assessment of T cell responses. Immobilized B cells were washed out of the column and enzymatically released from the beads.
To detect the IgG+ B cells specific for the omicron and wild-type SARS-CoV-2 RBD the magnetically isolated B cells were resuspended in FACS buffer (PBS supplemented with 2% FCS, 0.05% NaN3, and 2mM EDTA) and incubated with the fluorescently labeled recombinant RBD proteins (Biotinylated SARS-CoV-2 Spike RBD Protein, Acrobiolabs, SPD-C82E8 and Biotinylated SARS-CoV-2 Spike RBD (B.1.1.529/Omicron), Acrobiolabs, SPD-C82E4). The wild-type RBD protein was conjugated with streptavidin-PE (Biolegend, 405204) and omicron RBD with streptavidin-APC (Biolegend, 40520). 15min into incubation with RBD proteins, an anti-IgG-BV421 antibody (clone G18-145, Biolegend, 562581, diluted 1:20) was added and the incubation was continued for another 15min. Cells were then washed with PBS and stained for viability (ZombieAqua, Biolegend, 423102) for 15min at 4C. Afterward, cells were washed with FACS buffer and incubated with a solution of antibodies blocking human Fc receptors (FcR block, Miltenyi Biotec, 130-059-901, diluted 1:10) for 10min at 4C. Next, a mixture of fluorescently labeled antibodies consisting of: anti-CD3-BV510 (clone UCHT1, Biolegend, 300448, diluted 1:40), anti-CD27-BV605 (clone O323, Biolegend, 302830, diluted 1:20), anti-IgM-BV785 (clone MHM-88, Biolegend, 314544, diluted 1:20), anti-IgA-VioBright 515 (clone REA1014, Miltenyi Biotec, 130-116-886, diluted 1:40), anti-CD21-PE-Cy7 (clone Bu32, Biolegend, 354912, diluted 1:160), and anti-CD19-APC-Cy7 (clone HIB19, Biolegend, 302218, diluted 1:80) was added. Each antibody was checked for performance and titrated before use. Following incubation at 4C for 15min, the cells were washed again and acquired on a BD FACS Celesta flow cytometer with BD FACSDiva Software Version 8.0 (BD Bioscience). Possible longitudinal fluctuations in laser intensity were monitored daily before the experiment using fluorescent beads (Rainbow beads, Biolegend, 422905). The data were analyzed with the FlowJo Software version 10.0.7 (TreeStar). To compensate for the background binding of IgG+ B cells to the fluorescent probes 16 samples were stained with unconjugated streptavidin-PE/APC. The average frequency of streptavidin-PE/APC-binding cells plus two standard deviations was subtracted from the frequencies of RBD-binding cells. No technical replicates were performed due to the scarcity of the samples.
B-cell-depleted PBMC fraction was seeded in 96-well U bottom plates and stimulated with two different pools of overlapping peptides: the first covering the mutated regions of the omicron SARS-CoV-2 spike protein (PepTivator SARS-CoV-2 Prot_S B.1.1.529/BA.1 Mutation Pool, Miltenyi Biotec, 130-129-928) and the second covering conserved regions of the spike (PepTivator SARS-CoV-2 Prot_S B.1.1.529/BA.1 WT Reference Pool, Miltenyi Biotec, 130-129-927). One million cells were stimulated per condition. The final concentration of each peptide was 1g/ml for both peptide pools. Co-stimulatory antibodies (BD FastImmune CD28/CD49d, BD Bioscience, 347690) were added to a final concentration of 1g/ml. For each sample, an equally treated DMSO-stimulated negative control was included. As a positive control, cells were stimulated with PMA (20ng/ml) (Sigma-Aldrich, P1585-1MG) and ionomycin (1g/ml) (Sigma-Aldrich, I3909-1ML). Stimulation was performed at 37C for 6hours. One hour into stimulation Golgi Stop (BD Bioscience, 554724) and Golgi Plug (BD Bioscience, 555029) were added (final concentration 1g/ml) to inhibit vesicular transport and prevent the secretion of the cytokines from cells.
Stimulated cells were washed with PBS and stained for viability (ZombieAqua, Biolegend, 423102) for 15min at 4C. Subsequently, samples were washed with FACS buffer, fixed, and permeabilized in CytoFix/CytoPerm Solution (BD Bioscience, 554714) for 15min at 4C. Fixed cells were washed with 1x Perm/Wash Buffer (BD Bioscience, 554723), and stained for the following intracellular markers; anti-CD3-APC-Cy7 (clone UCHT1, Biolegend, 300426, diluted 1:40), anti-CD4-BV786 (clone SK3, BD Bioscience, 344642, diluted 1:40), anti-CD8-PE-Cy7 (clone SK1, Biolegend, 344712, diluted 1:80), anti-IFN-PE (clone B27, Biolegend, 506507, diluted 1:40), and anti-TNF-BV421 (clone Mab11, Biolegend, 502932, diluted 1:80). Each antibody was checked for performance and titrated before use. Following 15min incubation at 4C, cells were washed thrice with PBS and acquired on a BD FACS Celesta with BD FACSDiva Software Version 8.0 (BD Bioscience). To minimize the signal from unspecific staining only T cells expressing IFN and TNF were considered antigen-specific. The frequencies of antigen-specific T cells were calculated as negative-control-subtracted data. Possible longitudinal fluctuations in laser intensity were monitored daily before the experiment using fluorescent beads (Rainbow beads, Biolegend, 422905). If needed PMT voltages were adjusted to ensure constant signal intensity over time. The data were analyzed with the FlowJo Software version 10.0.7 (TreeStar). No technical replicates were performed due to the scarcity of the samples.
Statistical analysis was performed using GraphPad Prism software version 9.4.1. (681). Differences between the groups were assessed using the Kruskal-Wallis test with Dunns correction for multiple testing. All tests were performed two-sided. Statistical significance is indicated by the following annotations: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.
Further information on research design is available in theNature Portfolio Reporting Summary linked to this article.
Dr. Reddys has entered into an exclusive partnership with Sanofi Healthcare India to promote and distribute their vaccine brands across private markets in India.
Dr. Reddys will have exclusive rights to promote and distribute Sanofis pediatric and adult vaccine brands Hexaxim, Pentaxim, Tetraxim, Menactra, FluQuadri, Adacel and Avaxim 80U.
These brands saw combined sales of approximately $51 million, per IQVIA February 2024 data.
Sanofi will continue to own, manufacture and import these brands to the country.
Preeti Futnani, general manager India for vaccines at Sanofi, said, Vaccine confidence has reached its highest in India in the last few years. Yet, there is much to be done for the rest of the countrys large unvaccinated cohort. To fulfill our long-term commitment to India and expand our geographic reach, were pleased to partner with Dr. Reddys for exclusive distribution and promotion. Were confident this partnership will further bolster our promise of saving millions of lives against vaccines preventable diseases with improved vaccination coverage.
[Read more: Dr. Reddy's acquires MenoLabs from Amyris]
M.V. Ramana, CEO of branded markets (India and emerging markets), at Dr. Reddys, said, We are happy to have the opportunity to leverage our strengths in promotion and distribution to considerably expand engagement with healthcare professionals and help widen access of Sanofis well-established and trusted vaccine brands in India. We continue our efforts to become the partner of choice in bringing novel, innovative and trusted drugs to patients in India through strategic collaborations. The portfolio now gives Dr. Reddys a strong presence in the vaccine segment, propelling us to the second position among vaccines players in India. Through each product and partnership, our aim is to serve over 1.5 billion patients by 2030.
[Focus On: How Dr. Reddys Labs approach sets it apart in a crowded space]
