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Why's there no vaccine against Respiratory Syncytial Virus (RSV)?

Why's there no vaccine against Respiratory Syncytial Virus (RSV)?


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RSV was discovered in 1956. Here's why we can't rush a COVID-19 vaccine | AAMC

Respiratory syncytial virus (RSV): This pervasive respiratory virus has proven resistant to vaccination. Children treated with one vaccine in the 1960s developed an enhanced form of the disease, suffering high fever, bronchopneumonia, and wheezing. Many were hospitalized and two died.

“That set the field back years,” Poland said, as researchers and manufacturers “were afraid” to try again.

Researchers have since tried but still not developed an RSV vaccine for public use, according to the CDC. Babies at particularly high risk for RSV are sometimes injected with an antibody to help fight off infection.

I don't grasp the Canadian government's Overview of the respiratory syncytial virus vaccine candidate pipeline in Canada, CCDR 46(4). E.g. so what if "amino acids do vary in prefusion specific epitopes"?

Challenges to RSV vaccine development

Antigen diversity

A successful vaccine candidate will account for the diversity of antigens presented by RSV in the form of the structural variability of the proteins on the surface of the virus. The protective, neutralizing antibody response to RSV is dominated by antibodies targeting the prefusion F protein on the surface of RSVFootnote 17Footnote 18. Although the genetic sequence of F does not vary substantially between strains of RSV [89% of its sequence is identical in both A and B strainsFootnote 19], amino acids do vary in prefusion specific epitopes [bolding mine]. As new products are authorized and make it into broad usage, it will be critical to understand the sero-epidemiological responses at a population level to understand whether prefusion or postfusion antibodies are dominant responses, and whether these demonstrate equivalent protection against both RSV type A and B.

RSV infection dampens the immune response

[… ]

There are no clear correlates of protection

[… ]


RSV has been a difficult virus to create a vaccine against, though an experimental vaccine has finally been developed and is being tested by the University of Texas at Austin. Your article with Canada is probably talking about how certain amino acids and antibodies seem to be effective against the virus. However, this virus is a strange beast that is hard to treat. A potential vaccine was tested in the 1960s, but all it did was increase the rate of infection for the RSV, leading to some scientists classifying RSV as "immunopotentiation" or vaccine-enhanced. Normally, a vaccine contains a dead version of the virus or weakened byproducts of the virus to create a strong immune response to defeat a virus. However, with RSV, this process tends to make the viral infection worse. Hopefully, this new vaccine will yield results (and even if it doesn't, a medication called palivizumab can be given to babies and children to protect against the virus).


In answer to the specific question, This paper https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741363/ is the one the review was talking about.

The epitope that is targeted (the F protein) varies between strains, so a produced vaccine would only work on that strain. The protein (an obvious vaccine target) was selected because it exists on all strains, and is needed for the virion to fuse with the human cell.

In the vaccine The F protein epitope is fused with an immunostimulatory particle to get a good immune response. That's why they mention "prefusion" and "postfusion". There is confusion in the terminology because the F protein is so-named because of its role in fusing the virion to the cell.


Respiratory syncytial virus vaccine

A respiratory syncytial virus vaccine (RSV vaccine) is a vaccine which prevents infection by respiratory syncytial virus. No licensed vaccine against RSV exists at this time, although there is at least one vaccine candidate currently in clinical trials. [1]

Attempts to develop an RSV vaccine began in the 1960s with an unsuccessful inactivated vaccine developed by exposing the RSV virus to formalin (formalin-inactivated RSV (FI-RSV)). [2] Unfortunately, this vaccine induced a phenomenon that came to be known as vaccine-associated enhanced respiratory disease (VAERD), in which children who had not previously been exposed to RSV and were subsequently vaccinated would develop a severe form of RSV disease if exposed to the virus itself, including fever, wheezing, and bronchopneumonia. [2] Some eighty percent of such children (vs. 5% of virus-exposed controls) were hospitalized, and two children died lethal – lung inflammatory response during the first natural RSV infection after vaccination of RSV-naive infants. [2] This disaster hindered vaccine development for many years to come. [2]

A 1998 paper reported that research toward developing a vaccine had advanced greatly over the previous 10 years. [3] The desired vaccine would prevent lower respiratory infection from RSV in at-risk populations and if possible be useful in other populations with less risk. [3] Twenty years later, a 2019 paper similarly claimed that research toward developing a vaccine had advanced greatly over the prior 10 years. [4] The same study predicted that a vaccine would be available within 10 years. [4]

The current types of vaccines which are in research are particle-based vaccines, attenuated vaccines, protein subunit vaccines, or vector-based vaccines. [5]

The DS-Cav1 vaccine for RSV, a protein subunit vaccine, was shown to be safe and to elicit “a robust boost in RSV F-specific antibodies and neutralising activity that was sustained above baseline for at least 44 weeks” in a phase 1 clinical trial, according to a study published in April 2021 in The Lancet Respiratory Medicine. [1] A vaccine using this antigen, called GSK3888550A and developed by GlaxoSmithKline (GSK), is currently in phase 3 clinical trials, which began in November 2020. [6] Barney S. Graham and Peter Kwong of the National Institute of Allergy and Infectious Diseases' Vaccine Research Center, along with Jason McLellan, a former postdoctoral researcher at VRC and now an associate professor at The University of Texas at Austin, spearheaded the development of DS-Cav1. [7] The vaccine’s antigen, a stabilized version of the virus’ F protein, was developed using structure-based vaccine design. [8] [9] [10]


Respiratory syncytial virus vaccine enters clinical testing

NIH-led trial to evaluate RSV vaccine’s safety in healthy adults.

“A vaccine to reduce the burden of this important disease is badly needed.”

Anthony S. Fauci, M.D., Director, NIAID

A Phase 1 clinical trial to test the safety and tolerability of an investigational vaccine against respiratory syncytial virus (RSV) has begun at the National Institutes of Health Clinical Center in Bethesda, Maryland. The trial also will assess the vaccine’s ability to prompt an immune response in healthy adult participants. The investigational vaccine was developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH.

Most people are infected with RSV by age 2 and undergo repeated infections throughout life. Infected adults and children generally experience mild, cold-like symptoms that resolve within a week or two. However, infection can cause severe lower respiratory tract disease, including pneumonia and bronchiolitis, among premature infants, children younger than age 2 with heart or lung problems, children and adults with weakened immune systems and the elderly. About 2 percent of RSV-infected infants under 1 year of age require hospitalization. Children between ages 1 and 5 years and adults older than 65 years are also at higher risk of hospitalization.

Each year on average in the United States, RSV leads to 57,527 hospitalizations and 2.1 million outpatient visits among children younger than 5 years and 177,000 hospitalizations and 14,000 deaths among adults older than 65 years, according to the Centers for Disease Control and Prevention. Globally, RSV infections are estimated to cause more than 250,000 deaths each year.

Currently no vaccine to prevent RSV infection or drug to treat it is available. The monoclonal antibody palivizumab is licensed in the U.S. for preventing serious lower respiratory tract disease caused by RSV in high-risk children, but it is not licensed for use in the general population.

“RSV is underappreciated as a major cause of illness and death, not only in infants and children but also in people with weakened immune systems and the elderly,” said NIAID Director Anthony S. Fauci, M.D. “A vaccine to reduce the burden of this important disease is badly needed.”

The study, called VRC 317, will enroll healthy adults ages 18-50 years. Participants will be randomly assigned to receive two injections in the arm at 12 weeks apart with either the investigational vaccine or the investigational vaccine adjuvanted with alum. Alum is a chemical compound commonly added to vaccines to enhance the body’s immune response.

Participants will also be randomly assigned to receive one of three vaccine doses (50 micrograms, 150 micrograms or 500 micrograms) at both vaccination time points. Initially, five people will be vaccinated with the 50 microgram dose. If the initial group of participants experience no serious adverse reactions attributable to the vaccine, the study team will then begin to vaccinate participants at the next dosage level. They will repeat this stepwise process until they administer the 500 microgram dose.

Participants will return for 12 clinic visits over 44 weeks after the first injection. At these visits, study clinicians will conduct physical exams and collect blood samples. They will also test mucous samples from volunteers’ mouths and noses to measure the immune responses generated.

The study is being led by principal investigator Michelle C. Crank, M.D., head of the Translational Sciences Core in the Viral Pathogenesis Laboratory part of NIAID’s Vaccine Research Center (VRC). Study clinicians will conduct a daily safety review of any new clinical information, and a Protocol Safety Review Team will examine trial safety data weekly to ensure the vaccine meets safety standards.

The investigational vaccine, called DS-Cav1, results from years of research led by Barney S. Graham, M.D., Ph.D., deputy VRC director, and Peter D. Kwong, Ph.D., chief of the Structural Biology Section and the Structural Bioinformatics Core at the VRC. The vaccine candidate is a single, structurally-engineered protein from the surface of RSV rather than a more traditional approach based on a weakened or inactivated whole virus. In 2013, VRC scientists tested several versions of the protein as a vaccine in mice and nonhuman primates. The protein variants elicited high levels of neutralizing antibodies and protected the animals against RSV infection. Drs. Graham and Kwong selected the most promising candidate, DS-Cav1, for clinical evaluation.

“This work represents an example of how new biological insights from basic research can lead to candidate vaccines for diseases of public health importance, and the value of multidisciplinary research teams like the ones assembled at the VRC,” said Dr. Graham.

The trial is expected to take one year to complete. For more information about the trial, visit clinicaltrials.gov and search identifier NCT03049488. For more information, visit about NIAID’s Respiratory Syncytial Virus (RSV) web page.

NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.


Experimental Vaccine Against Respiratory Syncytial Virus (RSV) Elicits Strong Immune Response

An experimental vaccine against respiratory syncytial virus (RSV), one of the leading causes of infectious disease deaths in infants, has shown early promise in a Phase 1 human clinical trial. A team of researchers, including The University of Texas at Austin's Jason McLellan, report today in the journal Science that one dose of their vaccine candidate elicited large increases in RSV-neutralizing antibodies that were sustained for several months.

People contract RSV in all stages of life, but it's most dangerous in the very young and the very old. The virus causes pneumonia, bronchiolitis and other lower respiratory tract diseases. Every year, millions of people become sickened by RSV, and more than 100,000 die, mostly in areas that lack access to modern medical care. For infants under 1 year of age, RSV is second only to malaria for infectious disease deaths.

Barney Graham and Peter Kwong of the National Institute of Allergy and Infectious Diseases' Vaccine Research Center (VRC), along with McLellan, a former postdoctoral researcher at VRC and now an associate professor at UT Austin, spearheaded the development of the vaccine candidate DS-Cav1.

Scientists have tried to create an RSV vaccine using traditional methods for more than 50 years — and so far, none has worked. Instead, McLellan and his colleagues took a new approach, called structure-based vaccine design.

It was already known that a certain part of RSV, called the F protein, triggers the human immune system to produce antibodies. But the F protein is a shape shifter — before it infects a cell, it takes one shape and then during infection, it shifts to a second shape. If the immune system encounters an RSV virus with the F protein in the first shape, it makes potent antibodies. But if the protein is in the second shape, fewer antibodies are elicited, and they are not very effective. Producing RSV vaccines using traditional methods usually leads to F proteins in the second shape and a poor antibody response.

This is where the structure-based approach comes in. First, the researchers used a technique called X-ray crystallography to determine the atomic-level structure of the F protein in the first shape. Next, they re-engineered the F protein to take away its shape-shifting ability, locking it in the shape that elicits the best antibodies.

In 2013 they tested several versions as a vaccine in both mice and nonhuman primates. These protein variants elicited high levels of neutralizing antibodies and protected the animals against RSV infection.

"Our first time testing these stabilized molecules in animals, the response was 10-fold higher than anything anyone had ever seen before," McLellan said. "And at that point, we're thinking, 'This is it. We've got it.' That was exciting."

The most promising of these vaccine candidates, DS-Cav1, was selected for clinical evaluation and subsequently manufactured by the VRC.

The Science report is an interim analysis of data from the first 40 healthy adult volunteers enrolled in the trial, which began in the National Institutes of Health Clinical Center in 2017. Researchers found that the vaccine candidate elicits a greater than 10-fold increase in RSV-neutralizing antibodies, compared with the number of antibodies a person produces naturally from RSV exposure earlier in life.

The results are promising, but McLellan is careful to put them in perspective.

"The Phase 1 just asks: Is it safe and is it eliciting the types of antibodies and response that we were hoping to see?" he said. "It still needs to go through Phase 2 and Phase 3, looking at efficacy such as, is it reducing the severity of disease, or is it reducing hospitalizations?"

Many drugs fail to make it all the way through clinical trials. But if this one does, or another based on the same F protein structure that he helped discover, McLellan says it could be a game changer.

"If it works reasonably well and we prevent 70 to 80 percent of all deaths, just think of all the little infants and toddlers we'd save," McLellan said. "There aren't that many vaccines in the world, and so if we're able to actually participate in making one that works and saves lives, that would be awesome."

Additional information about the Phase 1 trial of DS-Cav1 (also known as VRC 317) is available at clinicaltrials.gov by using the trial identifier NCT03049488. Final results of the trial are expected next year.

The University of Texas at Austin is committed to transparency and disclosure of all potential conflicts of interest. The university investigator involved in this research, Jason McLellan, has submitted required financial disclosure forms with the university. McLellan is an inventor on several patent applications related to this research filed by the National Institutes of Health, from which he is receiving royalties.


Results

Construction and purification of the GcfAB subunit vaccine

To develop the dual subunit vaccine covering both subtypes (A and B) of RSV, we employed a strategy that fuses a highly-conserved central region (a.a. 131–230) of the RSV A2 G sequence with that of the RSV B1 G sequence, resulting in a GcfAB fusion in the pET-21d vector (Fig 1A). It was previously shown that a.a. residues 183–195 of GcfA functions as a CD4 T-cell epitope that is necessary for induction of a strong antibody response, while the same region of GcfB lacks T-cell epitope functionality and induces a relatively weak antibody response [29]. Thus, we reasoned that fusion of the GcfA sequence to the GcfB sequence might simultaneously provoke T-cell activity against both GcfA and GcfB, and thus, that immunization with the GcfAB fusion antigen might induce strong humoral responses against both subtypes. To this end, the GcfAB protein was purified from E.coli by His-tag affinity chromatography and size-exclusion chromatography, and its purity was confirmed using SDS-PAGE. The approximate molecular weight of the monomeric form of GcfAB is

33 kDa (black arrow) on SDS-PAGE under reducing conditions (Fig 1B).

Schematic diagram of the GcfAB recombinant protein. (A) A pET-21d plasmid containing both a.a 131 to 230 of RSV A2 G protein (GcfA) and a.a. 131 to 230 of RSV B1 G protein (GcfB) was constructed. (B) The GcfAB protein was purified by His-tag affinity chromatography (lane 1) and size-exclusion chromatography (Sephacryl S-200 HR) with (lane 2) / without (lane 3) dithiothreitol (DTT). Purification of GcfAB was confirmed by SDS-PAGE at each purification step, as indicated by the arrow.

Humoral antibody responses in GcfAB-immune mice

In order to investigate whether mucosal GcfAB immunization can elicit an antibody responses against both RSV A and B subtypes, BALB/c mice were immunized twice via intranasal (IN) or sublingual (SL) routes with 20 μg of GcfAB plus 2 μg of CT as a mucosal adjuvant (Fig 2A). Twenty-one days after immunization, RSV G-specific serum IgG antibody responses were measured by ELISA. Both the GcfAB IN and SL groups exhibited significant subtype A-specific serum IgG responses compared to the negative control PBS group (Fig 2B), but statistically significant differences between GcfAB IN and SL groups were not found (p = 0.1). The GcfAB IN and SL groups also exhibited subtype B-specific serum IgG responses (Fig 2C) GcfAB IN group induced significantly higher responses than both GcfB IN and GcfAB SL groups (p < 0.01), but GcfAB SL group did not differ significantly from the GcfB IN group (p = 0.4). The GcfA SL group and the GcfB IN group exhibited subtype-specific IgG responses (Fig 2B and 2C).

(A) The scheme used for animal experiments is shown in Fig 2. (B and C) Twenty-one days after the last immunization, RSV G-specific IgG titers in sera were measured by ELISA. GcfA (50 ng/well) or GcfB (100 ng/well) proteins were used as coating antigens, and goat anti-mouse IgG-HRP was used as a detection antibody. The cutoff optical density at 450 nm (OD 450 nm) was < 0.15 for a PBS negative result. (D and E) Five days after RSV A2 or B (KR/B/10-12) challenge, BAL fluid was harvested and the GcfA-specific or GcfB-specific mucosal IgA antibody responses were measured by ELISA. The results represent log2 endpoint values averaged from four mice. N.D., not detected. All data are expressed in mean ± SD (n = 4/group). Significant differences from the PBS control group are marked with asterisks (*). p < 0.01.

We next analyzed the secretory IgA antibody response following mucosal GcfAB vaccination. Mucosal IgA is important in the defense against respiratory virus infections, and is also associated with protective immunity against RSV infection [30]. To this end, GcfAB-immunized mice were challenged with RSV A (A2) or B (KR/B/10-12). GcfA SL and vvG were used as a positive controls for RSV A2 challenge and GcfB IN was used as a positive control for RSV B challenge. At 5 days post-challenge, the RSV A (Fig 2D) or RSV B (Fig 2E) subtype-specific mucosal IgA responses were measured by ELISA using bronchoalveolar lavage (BAL) fluid collected from each group. GcfA SL group induced RSV A-specific IgA response, and vvG group also induced RSV A-specific IgA response (Fig 2D). The levels of GcfA- or GcfB-specific mucosal IgA were significantly higher in the GcfAB IN and SL groups than PBS group (Fig 2D and 2E). Especially, GcfAB IN group elicited significantly higher GcfB-specific mucosal IgA response than GcfAB SL group against RSV B challenge (Fig 2E). The GcfB IN group also induced GcfB-specific mucosal IgA response, but it was not statistically different among the GcfAB-immune groups (Fig 2E). There was no detectable level of mucosal IgA antibody in the PBS group (negative control) against both RSV A and RSV B. Taken together, these results show that GcfAB immunization via either IN or SL routes effectively induces both RSV subtype-specific serum IgG and mucosal IgA antibody responses.

Epitope-specific antibody responses were induced by GcfAB immunization

Previous studies have shown that the RSV G protein contains several linear B cell epitopes [19, 31]. As these epitopes are present in the central conserved region of the RSV G protein [17], we expect that GcfAB can induce a variety of epitope-specific antibody responses. We investigated the epitope-specific antibody responses following GcfAB mucosal immunization. We performed ELISA using biotinylated peptides spanning residues 144–159, 164–176, 174–187 [32], and 190–204 of RSV A2 (Fig 3). The GcfAB IN group induced higher G/144-159 and G/164-176 peptide-specific serum IgG responses than did the GcfAB SL group (Fig 3A and 3B). Notably, G/174-187-specific serum IgG response was significantly higher in the GcfAB IN group than in the GcfAB SL group, in which the response was barely detectable above background levels. However, G/190-204-specific serum IgG response was reversed GcfAB SL group showed higher G/190-204-specific antibody response than that of GcfAB IN group (Fig 3A) but there was no significant difference (Fig 3B). These results indicate that the antibody responses to G/164-176 peptide are dominantly induced both in GcfAB IN and SL groups, and IN immunization generally elicits higher levels of all epitope-specific antibody responses except for G/190-204 peptide than in SL immunization. By contrast, G/190-204-specific antibody response was generally weaker than other peptides-specific responses. Furthermore, we can expect that the types of epitope-specific antibody responses may be different depending on the administration routes, even with the same antigen.

BALB/c mice (n = 4/group) were immunized via intranasal or sublingual routes with 20 μg of GcfAB and 2 μg of CT. (A and B) After a booster immunization, peptide-specific IgG titers were determined in mouse sera. Biotinylated G peptides (a.a. 144–159, 164–176, 174–187 and 190–204 of the RSV A2 subtype) were used as a coating antigen (200 ng/well), and goat anti-mouse IgG-HRP was used as a detection antibody.

RSV A-specific CD4 T-cell responses are induced in GcfAB-immune mice after RSV A2 challenge

To analyze whether mucosal GcfAB vaccination primes RSV G-specific CD4 + T-cell responses, GcfAB-immune mice were challenged with 1×10 6 PFU of RSV A2 and lung cells were harvested 5 and 7 days post-challenge. Lung lymphocytes were stimulated with the G/183-195 peptide of the RSV A subtype (WAICKRIPNKKPGKK) for 5 hours ex vivo, and the levels of both IFN-γ and IL-17A were measured by flow cytometry (Fig 4A). After G/183-195 peptide stimulation, GcfAB-immune groups induced both IFN-γ + (

3% of total lung CD4 T cells on average) and IL-17A + CD4 T cells (25%

40% of total lung CD4 T cells on average) compared to the PBS group (Fig 4B). Interestingly, GcfAB SL group showed a significantly higher IL-17A + CD4 T-cell response than did the GcfAB IN group (Fig 4B). The vvG group as a positive control, showed strongest IFN-γ + CD4 T-cell response (about 20% of total CD4 T cells on average), but did not exhibit noticeable IL-17A + CD4 T-cell response (Fig 4B). In contrast, GcfAB-immune groups induced relatively weak IFN-γ + CD4 T-cell responses at 5 and 7 days post-challenge, compared with vvG group. Meanwhile, both the GcfAB IN and SL groups showed a similar responses in IFN-γ + and IL-17A + double-positive CD4 T cells (data not shown). This result indicates that mucosal GcfAB immunization induce Th17-type dominant CD4 + T-cell responses, and noticeably, SL immunization elicited stronger Th17-cell responses than did IN immunization.

Five and 7 days after RSV A2 challenge, lung mononuclear cells were isolated from GcfAB-immune mice. Cells were stimulated with PMA (50 μg/ml) and ionomycin (500 μg/ml) as a positive control, or with/without RSV G (a.a. 183–195 of RSV A2 subtype) peptide for 5 hours. Lung cells were stained for anti-CD3, CD4, IFN-γ, and IL-17A antibodies, and were analyzed by flow cytometry. (A) Cells gated for CD3 + CD4 + are shown in dot plots, (B) and the percentage is represented as the frequency of RSV G-specific IFN-γ + and IL-17A + CD4 T cells. Data are represented in mean ± SD (n = 4/group). Significant differences from the PBS group are marked with asterisks (*, **). p < 0.05.

CD4 T-cell responses for RSV B in GcfAB-immune mice after RSV B challenge

Next, in order to investigate whether GcfAB elicits CD4 T-cell responses upon RSV B subtype infection, GcfAB-immune mice were challenged with an RSV B (KR/B/10-12) clinical isolate with the same 131–230 amino acid sequence as GcfB. Five days post-challenge, GcfAB-immune mice were sacrificed and lung lymphocytes were stimulated with the G/183-195 peptide of the RSV B subtype (KSICKTIPSNKPKKK) which corresponds to the CD4 + T-cell epitope of GcfA. After 5 hours, the levels of IFN-γ- and IL-17A-expressing CD4 T cells were measured by flow cytometry (Fig 5A) in the same manner as in Fig 4. Both IFN-γ- and IL-17A-expressing cells were significantly fewer following RSV B G peptide stimulation (Fig 5B) as compared to those seen following RSV A2 G peptide stimulation after RSV A challenge (Fig 4B). These results indicate that a.a. residues 183–195 of the RSV B G protein do not play roles as CD4 + T-cell epitopes, as previously reported [29]. Consequently, CD4 T-cell responses for the RSV B subtype were not found in our study.

After RSV B (KR/B/10-12) challenge, all mice (n = 4/group) were sacrificed and lung mononuclear cells were isolated 5 days post-infection. Lung lymphocytes were stimulated and were analyzed as the same manner as in Fig 4. (A) CD3 + and CD4 + cells are shown in the dot plots, (B) and the percentage of such cells is represented as the frequency of RSV G-specific IFN-γ + and IL-17A + CD4 T cells. Data are represented in mean ± SD (n = 4/group). Significant differences are marked with a hash tag (#, p < 0.05).

Protective efficacy of GcfAB vaccine against both RSV A and B subtype infections

Since GcfAB immunization via different mucosal routes (IN and SL) induced significant humoral and cellular immune responses, we next investigated whether mucosal GcfAB immunization provides protection against both subtype infections. To this end, GcfAB-immune mice were challenged with RSV A (A2 strain) or RSV B (KR/B/10-12 strain), and the efficacy was measured by performing a standard plaque assay with lung samples 5 days post-challenge (Fig 6). As shown in Fig 6, GcfAB immunization protected mice against both RSV A (Fig 6A) and RSV B subtype (Fig 6B) challenge. vvG (as a positive control for RSV A subtype challenge) and GcfB+CT (as a positive control for RSV B subtype challenge) defended against each subtype. This result indicates that GcfAB immunization via both the IN and SL routes can provide protection against both the RSV A and B subtypes.

All mice (n = 4/group) were challenged with (A) 1×10 6 PFU/mouse of RSV A2 or (B) 2–4×10 6 PFU/mouse of RSV B (KR/B/10-12). Five days post-challenge, lung viral titer was determined by a plaque assay. The limit of detection is 100 PFU/g of lung tissue. N.D., not detected. Data are represented in mean ± SD (n = 4/group). Significant differences from the PBS group are marked with asterisks (*), p < 0.01.

Vaccine-enhanced pulmonary cell infiltration in GcfAB-immune mice after both RSV A and B subtype challenge

According to previous reports, RSV G-expressing vaccine candidates, such as vvG or subunit vaccines, consisting in part of the RSV G protein, showed excessive pulmonary eosinophilia following live RSV infection [14, 15, 18]. To investigate whether GcfAB immunization leads to pulmonary cell infiltration, GcfAB-immune mice were challenged with either RSV A2 (Fig 7) or RSV B (KR/B/10-12) (Fig 8). Five and 7 days post-challenge, we measured the percentages of both eosinophils and neutrophils in bronchoalveolar lavage (BAL) cells by flow cytometry (Figs 7A and 8A). After RSV A subtype challenge, the GcfAB SL group exhibited greater recruitment of eosinophils than did the GcfAB IN group, and the number of eosinophils was increased at 7 days compared to 5 days (Fig 7B). The vvG immune group (positive control) showed a significantly increased number and percentage of eosinophils, while the PBS group did not exhibit any detectable eosinophil recruitment (Fig 7B). The percent of neutrophils was significantly reduced in the GcfAB-immune groups compared with the PBS group at 7 days (Fig 7C), but both the percentage and number of neutrophils were not significantly different between the PBS and GcfAB-immune groups (p > 0.05) at 5 days (Fig 7C).

After two rounds of GcfAB vaccine administration, the GcfAB-immune groups were challenged with RSV A2 and then sacrificed at 5 and 7 days post-challenge. (A) BAL cells were harvested and then stained with anti-CD45, Siglec-F, Gr-1, and CD11c antibodies and analyzed by flow cytometry. (B and C) Eosinophils and neutrophils among CD45 + -gated cells were quantitated. All data represented in mean ± SD (n = 4/group). Significant differences from the PBS group are marked with asterisks (*). p < 0.05.

After two rounds of GcfAB vaccine administration, GcfAB-immune mice were challenged with RSV B (KR/B/10-12) and sacrificed for analysis 5 days post-challenge. (A) BAL cells were harvested and stained with anti-CD45, Siglec-F, Gr-1, and CD11c antibodies and then analyzed by flow cytometry. (B and C) Eosinophils and neutrophils among CD45 + - gated cells were quantitated. Data are expressed in mean ± SD (n = 4/group). Significant differences from the PBS group are marked with asterisks (*). p < 0.05.

Meanwhile, following RSV B subtype challenge, overall, both the numbers and percentages of eosinophils and neutrophils were lower than those of the GcfAB-immune groups challenged with the RSV A subtype. The GcfAB-immune groups showed a low level of eosinophils (< 0.1% of CD45 cells), but the GcfB IN group showed high level of eosinophil recruitment compared with the GcfAB-immune groups (Fig 8B). Neutrophils were induced in approximately a 3-fold greater extent in the GcfAB SL group than in the GcfAB IN group (Fig 8C). Taken together, these data indicate that SL immunization with GcfAB elicits significantly more vaccine-induced eosinophil infiltration than does IN immunization following RSV A challenge. On the contrary, GcfAB immunization induces low-level pulmonary cell infiltration upon RSV B subtype challenge, which probably leads to a very weak inflammatory response in the airways.

Vaccine-enhanced disease in GcfAB-immune mice after RSV A and B subtype challenge

We determined that GcfAB immunization provoked a different amount of vaccine-induced cellular infiltration in BAL (Fig 7) and lung tissue (Figs 4 and 5) depending on mucosal immunization route and subtype infection. So, we investigated whether the use of differential immunization routes results in any differences in vaccine-induced disease patterns following RSV subtype challenge. We have identified RSV A but not RSV B challenge causes pulmonary cell infiltration in GcfAB-immune mice (Figs 7 and 8). In order to determine the histopathology in the lung, we performed H&E and PAS staining on the lung tissues which were harvested at day 5 post-RSV A2 challenge (Fig 9A). Consistent with flow cytometric data, both GcfAB IN and SL groups induced inflammatory cell infiltrations compared to PBS group in the RSV A2 challenge. Noticeably, GcfAB SL group elicited higher degree of inflammatory cell infiltration than GcfAB IN group (Fig 9A, left column, 10× magnification). Higher degrees of airway mucus secretion and goblet cell hyperplasia were also induced in GcfAB SL group than in GcfAB IN group (Fig 9A, right column, 10× magnification). GcfAB-immune mice were challenged with RSV A2 or RSV B (KR/B/10-12) and body weight loss was monitored for 5 days after RSV challenge (Fig 9B and 9C). Following RSV A2 challenge (Fig 9B), the GcfAB SL group and the vvG group experienced significant weight loss compared with the PBS group. The GcfAB SL group showed rapid and severe weight loss until 3 days post-challenge, while body weight of the GcfAB IN group was slightly decreased at 1 day post-challenge and recovered from 2 days post-challenge onwards. Following RSV B subtype challenge (Fig 9C), however, both GcfAB-immune groups and the PBS group did not exhibit any significant decrease in body weight. The GcfB IN group showed a body weight decrease up to

8% on day 1 (Fig 9C). Together, these data demonstrates that SL immunization with GcfAB causes massive inflammatory cell infiltration and severe body weight loss when compared with IN immunization after RSV A challenge, but not after RSV B challenge.

To investigate cellular infiltration and mucus secretion in the lungs, we performed the (A) H&E staining (left column) and PAS staining (right column) of lung tissues which were harvested at 5 days post-RSV A2 challenge, and evaluated by light microscopy (10× magnification). Scale bar, 100 μm. Body weight was monitored for 5 days post-challenge with (B) 1×10 6 PFU of RSV A2 or (C) 2–4×10 6 PFU of RSV B (KR/B/10-12). Data are expressed in mean ± SD (n = 4/group).


RSV respiratory virus could be dangerous to young children, doctors warn

Reports from across the country reinforce what McGee has witnessed. Hospitals in New York, Kentucky, North Dakota, Louisiana and Ohio are all reporting more cases than usual.

Hospitals across the Chicago area are also reporting a spike in cases, NBC 5 Chicago reported. So many people are getting sick that emergency rooms are full and it takes hours just to be seen.

“RSV has arrived several weeks earlier than it usually does. We have seen many cases in our ICU and many children have been hospitalized,” Dr. Matthew Washam, medical director of epidemiology at Nationwide Children’s Hospital in Columbus, told TODAY. “It’s an atypical year for RSV in terms of severity.”

The experts are unsure why RSV season is more prevalent and serious this year. Some suggest that unusual and sudden changes in the weather — from warm to mild to cold, and from wintry mix to dry weather — could cause the virus to mutate.

Doctors urge parents to consider preventative measures, such as hand washing and staying home when sick, to counter the virus. There is no vaccine or treatment for RSV. Adults 65 and over, and those who have chronic heart or lung disease, or a weakened immune system are vulnerable, too.

“There are no supplements or nutrients or anything like that you can use and prevent it from happening,” McGee said. “Don't expect antibiotics because antibiotics don't play any role in the treatment.”

RSV shares many symptoms with the flu, though children with flu would be more likely to complain of fever or muscle aches, though that's not always the case. Doctors can test to see if children have flu, RSV or rhinovirus, aka the common cold. While most cases of RSV are mild and resolve themselves in a few days or weeks, some children become very ill.

“If your child is working hard to breathe, that can be quite serious and it needs to be addressed,” McGee said.

Children with RSV can develop bronchiolitis, which is “a lower respiratory tract infection.”

“RSV can cause severe disease in young children with risk factors, such as chronic lung disease, heart conditions or who are immunocompromised,” Washam said.

Even if children are hospitalized for RSV, doctors can only help them breathe better and have no medications that effectively treat it.

“All we have in our toolbox are ways to help the child breathe easier until their body fights off infection,” McGee said.


Discussion

Our analyses indicate that vaccination of children under 5 y of age could effectively and efficiently reduce RSV in young children and older adults. This impact of vaccinating children arises because children are disproportionately responsible for transmission, attributable to a combination of factors. First, children have higher infectious viral loads than adults, with longer durations of infection (22, 26, 27). Second, children have both greater frequency and duration of contacts than adults. Additionally, children are more likely to mix with individuals in their own age group, who are more susceptible to become infected with RSV. Specifically, although children under 5 y of age represent less than 10% of the US population, vaccinating these children with a 60% efficacious vaccine could reduce as much as 75% of RSV infection in children and the elderly combined.

RSV and influenza vaccines may be coadministered a clinical trial has already been completed to evaluate their safety together (24). A challenge is that the RSV season typically occurs earlier than the influenza season. Recent studies have demonstrated that protection conferred by the influenza vaccine wanes rapidly (28, 29). Thus, future studies should focus on optimizing the schedule of both influenza and RSV vaccination. As a component of such an optimization analysis, it should be taken into account that influenza infection results in more hospitalizations among the elderly, whereas RSV is responsible for more hospitalizations in young children. However, the indirect protection to the elderly from targeting children is substantial against both influenza (30, 31) and, as we have found, RSV.

We found that targeting children younger than 5 y of age is highly efficient per dose, and is also the most effective strategy to reduce RSV in both young children and older adults across all states and transmission settings. Nevertheless, vaccinating the rest of the population could further decrease the number of cases, albeit with substantially lower efficiency that varies across states. These results suggest that future cost-effectiveness analysis of RSV vaccination should be tailored to specific states.

Ongoing clinical trials on RSV for different age targeting do not explicitly consider the effect of indirect protection via reduced transmission (10). However, we found that the indirect protection arising from vaccinating children is so substantial that it is even predicted to avert more cases in older adults than would a vaccination program directly targeting the adults. This finding underscores the importance of measuring the infectious viral load and disease severity for vaccinated individuals who become infected, which can be assessed by swab tests and survey studies.

As for any modeling study, we made a number of simplifying assumptions. Because RSV is typically mild in older children and adults under 50 y of age, limited data are available on RSV incidence in these age groups. Nevertheless, even when we assumed an annual attack rate of 8.3% (SI Appendix), more than double the base case, vaccinating young children remained the most efficient and effective strategy. Given there is no commercially available vaccine against RSV, we were required to make certain assumptions about the potential vaccine and its uptake. For example, we assume that immune protection elicited by vaccination is equivalent to natural infection. We also assume that the efficacy of the vaccine is the same for all ages, whereas many vaccines have lower efficacy in the elderly (32, 33). Nonetheless, this assumption is conservative with regard to our finding that vaccinating children is much more effective and efficient than vaccinating the elderly.

In conclusion, allocating vaccine doses to children under 5 y of age is more effective not only for the children but also for older adults, due to reduced transmission. Our finding that indirect protection can avert even more infections than direct protection of adults over 50 y of age highlights the importance of accounting for population-level effectiveness rather than solely for individual-level efficacy. Given several types of vaccine candidates currently targeting different age groups (10, 11, 34), focusing on children is likely to be the most promising for reducing the incidence, morbidity, and mortality of RSV.


NIH scientists develop candidate vaccine against respiratory syncytial virus

IMAGE: The respiratory syncytial virus (RSV) is responsible for a common childhood illness. There is no vaccine available to prevent RSV infection. view more

An experimental vaccine to protect against respiratory syncytial virus (RSV), a leading cause of illness and hospitalization among very young children, elicited high levels of RSV-specific antibodies when tested in animals, according to a report in the journal Science.

Early-stage human clinical trials of the candidate vaccine are planned. Scientists from the Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, built on their previous findings about the structure of a critical viral protein to design the vaccine. The team was led by Peter D. Kwong, Ph.D., and Barney S. Graham, M.D., Ph.D.

In the United States, RSV infection is the most common cause of bronchiolitis (inflammation of small airways in the lungs) and pneumonia in children less than one year old and the most common cause for hospitalization in children under five. Worldwide, it is estimated that RSV is responsible for nearly 7 percent of deaths in babies aged 1 month to 1 year only malaria kills more children in this age group. Others at risk for severe disease following RSV infection include adults over age 65 and those with compromised immune systems.

"Many common diseases of childhood are now vaccine-preventable, but a vaccine against RSV infection has eluded us for decades," said NIAID Director Anthony S. Fauci, M.D. "This work marks a major step forward. Not only does the experimental vaccine developed by our scientists elicit strong RSV-neutralizing activity in animals, but, more broadly, this technique of using structural information to inform vaccine design is being applied to other viral diseases, including HIV/AIDS."

Earlier this year, the VRC team obtained atomic-level details of an RSV protein--called the fusion (F) glycoprotein--bound to a broadly neutralizing human RSV antibody. The protein-antibody complex gave scientists their first look at the F glycoprotein as it appears before it fuses with a human cell. In this pre-fusion shape, F glycoprotein contains a region vulnerable to attack by broadly neutralizing antibodies (antibodies able to block infection from the common strains of RSV).

Once RSV fuses with a cell, this vulnerable area, named antigenic site zero by the researchers, is no longer present on the rearranged F protein. In natural RSV infection, the immune system produces antibodies against both the pre-fusion and post-fusion forms of F glycoprotein, but the antibodies to antigenic site zero, which is only present on the pre-fusion form, have much stronger neutralizing activity. Therefore, a vaccine against RSV would have greater chance of success by eliciting antibodies directed at F glycoprotein in its pre-fusion configuration.

In their current publication, Drs. Kwong and Graham describe how they used this structural information to design and engineer F glycoprotein variants that retained antigenic site zero even when no antibody was bound to it. The goal was to create stable variants that could serve as the foundation for a vaccine capable of eliciting a potent antibody response. The researchers designed more than 100 variants of these, 3 were shown by X-ray crystallography to retain the desired structure. The engineered variants were then used as vaccines in a series of experiments in mice and rhesus macaques.

In both mice and macaques, the researchers found that the more stable the protein, the higher the levels of neutralizing antibodies elicited by vaccination. The levels of antibody made in response to one of the engineered F glycoproteins were more than 10 times higher than those produced following vaccination with post-fusion F glycoprotein and well above levels needed to protect against RSV infection.

"Here is a case in which information gained from structural biology has provided the insight needed to solve an immunological puzzle and apply the findings to address a real-world public health problem," said Dr. Graham. He and the VRC scientists are continuing to refine the engineered F glycoproteins and hope to launch early-stage human clinical trials of a candidate RSV vaccine as soon as clinical grade material can be manufactured, a process that takes about 18 to 24 months to complete.

"Previously, structure-based vaccine design held promise at a conceptual level," said Dr. Kwong. "This advance delivers on that promise and sets the stage for similar applications of structure-guided design to effective vaccines against other pathogens."

Dr. Fauci added, "This latest advance underscores the advantages of the VRC's organizational design, where experts in RSV virology, vaccinology and clinical studies, such as Dr. Graham, are in daily contact with Dr. Kwong and others who are experts in structural biology. Such close collaboration across disciplines allows for rapid testing of new approaches to a given problem."

NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www. nih. gov.

NIH. Turning Discovery Into Health

References:
JS McLellan et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science DOI: 10.1126/science.1243283 (2013).


Why ADE Hasn't Been a Problem With COVID Vaccines

by Veronica Hackethal, MD, MSc, Enterprise & Investigative Writer, MedPage Today March 16, 2021

Early in the pandemic, scientists engaged in a flurry of discussions about the best way to construct COVID-19 vaccines to ensure their efficacy and safety. Some of these discussions centered around antibody-dependent enhancement of immunity (ADE), a potentially deadly immune phenomenon seen with other viral infections and vaccines.

So far, there have been no reports of ADE with COVID-19 vaccines. But the concerns about ADE with COVID-19 vaccines have resurfaced with the emergency of virus variants. What exactly is ADE? What do we know from past experience with it? And why do experts say it's a non-issue with COVID-19 vaccines?

Features of ADE

While ADE can arise by different pathways, perhaps the best known is the so-called "Trojan Horse" pathway. This occurs when non-neutralizing antibodies generated by past infection or vaccination fail to shut down the pathogen upon re-exposure.

Instead, they act as a gateway by allowing the virus to gain entry and replicate in cells that are usually off limits (typically immune cells, like macrophages). That, in turn, can lead to wider dissemination of illness, and over-reactive immune responses that cause more severe illness, Barry Bloom, MD, PhD, of the Harvard T.H. Chan School of Public Health, told MedPage Today.

"The cause of ADE is having antibodies to a virus that don't neutralize it. That enables the virus to be gobbled up by cells that have receptors for antibodies, but not the virus. That's the way of getting virus into cells that it ordinarily would not infect," Bloom said.

ADE can also occur when neutralizing antibodies (which bind the virus and stop it from causing infection) are present at low enough levels that they don't protect against infection. Instead, they can form immune complexes with viral particles, which in turn leads to worse illness.

What Does Past Experience Tell Us About ADE?

The classic example of Trojan Horse-style ADE comes from dengue. This virus comes in four varieties. They are different enough from each other that past infection with one does not always generate antibodies that match well enough to protect against a different variety.

ADE has also occurred after vaccination for dengue. For example, in 2016 a dengue vaccine was developed to protect against all four serotypes and given to 800,000 children in the Philippines. Among children who were vaccinated and later exposed to wild-type dengue, 14 died, presumably from more severe illness. Since then, the vaccine has been recommended only to children 9 years and older who have already been exposed to dengue.

Another classic example comes from the U.S., when ADE occurred during a clinical trial for an inactivated vaccine against respiratory syncytial virus (RSV). In 1967, children who participated in the trial and received the vaccine developed more severe RSV illness when they later encountered the virus in the community. Two toddlers died. The vaccine was associated with immune complex formation that caused lung obstruction and enhanced respiratory disease, pretty much stalling RSV vaccine development.

Similarly, cases of ADE also occurred with an inactivated measles vaccine that was being developed in the U.S. in the 1960s. After vaccinated children developed more severe illness, the vaccine was withdrawn. The live, weakened measles vaccines that are currently in use in the U.S. have not been associated with ADE.

ADE a Non-Issue With COVID Vaccines

Scientists say that ADE is pretty much a non-issue with COVID-19 vaccines, but what are they basing this on?

From the early stages of COVID-19 vaccine development, scientists sought to target a SARS-CoV-2 protein that was least likely to cause ADE. For example, when they found out that targeting the nucleoprotein of SARS-CoV-2 might cause ADE, they quickly abandoned that approach. The safest route seemed to be targeting the S2 subunit of the spike protein, and they ran with that, wrote Derek Lowe, PhD, in his Science Translational Medicine blog "In the Pipeline."

Scientists designed animal studies to look for ADE. They looked for it in human trials, and they've been looking for it in the real-world data for COVID-19 vaccines with emergency use authorization. So far, they haven't seen signs of it. In fact, the opposite is happening, Lowe noted.

"[W]hat seems to be beyond doubt is that the vaccinated subjects, over and over, show up with no severe coronavirus cases and no hospitalizations. That is the opposite of what you would expect if ADE were happening," he wrote.

Furthermore, ADE is an acute problem, and it can be very dramatic. If it was an issue with these vaccines, we would have spotted it by now, said Brian Lichty, PhD, an associate professor in pathology and molecular medicine at McMaster University in Toronto.

"It'll kill you quickly. In all the places I'm aware of ADE happening, it is an acute, mostly cytokine-driven event," he told MedPage Today.

The one exception may be an inactivated whole-cell, or "killed," vaccine developed by China. That vaccine uses alum, the same adjuvant that was used in the measles and RSV vaccines that caused ADE in the 1960s. The Chinese inactivated whole-cell vaccine could "conceivably" generate ADE like those older vaccines, according to Bloom.

"I don't think that vaccine is ever going to see the light of day in the U.S., and it may not even be worth mentioning. There have been no actual cases of ADE with the Chinese whole-cell killed vaccine, or if so, it hasn't been reported," he said.

What About Variants?

Current COVID-19 vaccines were developed to protect against the original strain of SARS-CoV-2 that became dominant worldwide. As more variants arise, scientists have raised questions about whether one of these could become different enough to cause ADE. So far, that concern seems to be hypothetical, according to Lichty.

"To date, there's really no evidence of ADE with the COVID-19 vaccines. It's all theoretical," he said. "I think all the evidence so far is that ADE is not turning out to be a problem with any existing vaccines or viral variants."

One reason could be that SARS-CoV-2 just may not affect macrophages in a way that can produce ADE, although scientists are still working out the details. ADE has been reported after natural infection with other viruses, such as HIV, Ebola, and coxsackievirus, as well as other coronaviruses like SARS and MERS.

Throughout the pandemic, scientists have been looking for ADE associated with SARS-CoV-2, but so far they haven't found any cases of it, noted Lichty.

"This coronavirus may already be sufficiently adapted to humans, so that if it does get into macrophages via a non-neutralizing antibody interaction, it may not allow the macrophage to produce enough cytokine to cause an obvious pathology," he said.

Newer Vaccines Are Safer

Despite hesitancy about the relative newness of mRNA and adenoviral vector vaccines, these vaccines, in fact, have better safety profiles in terms of ADE than older types of vaccines, according to Bloom.

"The bottom line is that not only is the new technology faster to respond to a new viral pandemic, but so much safer and much more clearly scientifically designed," he said. "The S protein vaccines are so much cleaner, so much more carefully defined, and so much lower risk. All you're seeing is one protein from that virus. So the chances for ADE are much slimmer than with any of the older ways for making virus vaccines."

Veronica Hackethal reports for MedPage Today's Enterprise and Investigative journalism team. Follow


Vaccine against respiratory syncytial virus shows promise in early trial

Johns Hopkins Bloomberg School of Public Health researchers say a new candidate vaccine against respiratory syncytial virus (RSV) made with a weakened version of the virus shows great promise at fighting the disease, the leading cause of hospitalization for children under the age of one in the U.S.

There is currently no vaccine against RSV, which causes an estimated 66,000 to 199,000 deaths worldwide each year, and annual wintertime epidemics of respiratory illness in U.S. children.

Creating a vaccine with a live weakened virus - similar to what is used to prevent measles, mumps and rubella - requires a delicate balance: The virus must be weak enough so as not to make anyone sick and strong enough to induce a response from the body's immune system.

The researchers, who conducted a clinical trial that is reported in the Nov. 4 Science Translational Medicine, say they have used the virus' own machinery to create a vaccine that may protect young children from RSV disease. The vaccine, called MEDI ΔM2-2, is made from a genetically engineered version of the virus that is missing the gene for the M2-2 protein, a protein that acts like a switch. When M2-2 is deleted, the virus produces more of the viral proteins that trigger immune responses but less of the infectious virus that makes people ill.

"An RSV vaccine with this M2-2 deletion could tip the balance toward a better immune response, which is what we predicted based on earlier laboratory studies," says study leader Ruth A. Karron, MD, director of the Center for Immunization Research and a professor in the Department of International Health at the Bloomberg School. "From what we have seen in this small preliminary study in young children, this experimental vaccine is working as we hoped it would."

The vaccine, developed by the National Institutes of Health's Laboratory of Infectious Diseases at the National Institute of Allergy, Immunology and Infectious Diseases (NIAID), was sequentially evaluated in adults, older children who had previously been infected with RSV and infants and younger children who had not been exposed to the virus. The vaccine was given by nose drop, which allows development of immunity in the nose (where the virus initially takes hold) and throughout the body.

The study showed that the vaccine being tested elicited more RSV antibodies in young children than a previous RSV vaccine candidate. The study also provided very preliminary evidence that some vaccinated children had strong 'booster' antibody responses when they encountered RSV in the community, but without RSV illness that required medical attention.

"These early clinical data are exciting, and make us think differently about the development of live vaccines for RSV," Karron says. "If this research is borne out in future studies, we could be less than a decade away from a safe and effective live-attenuated vaccine for RSV."

As the use of vaccines to prevent bacterial pneumonia in children have become more widespread, the importance of developing a vaccine for RSV has become even clearer.

"It's the next mountain to climb in terms of serious respiratory illness in children," Karron says.

"A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children" was written by Ruth A. Karron Cindy Luongo Bhagvanji Thumar Karen M. Loehr Janet A. Englund Peter L. Collins and Ursula J. Buchholz.

The research was supported by NIAID contract HHS 27220090010C, the NIAID intramural program, a grant from the NIH's National Center for Advancing Translational Sciences (UL1TR000423) and a Cooperative Research and Development Agreement between NIAID, NIH and MedImmune.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.



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