US Pharm. 2022;47(4):33-38.

RSV Immunization for Healthy Infants Highly Effective in Phase III Trial

Nirsevimab showed 74.5% efficacy against medically attended lower respiratory tract infections caused by respiratory syncytial virus (RSV) in healthy infants, according to an international, randomized, placebo-controlled phase III clinical trial. It is the first potential immunization against RSV in the general infant population, with a single dose providing safe protection across the entire RSV season. Results were published in The New England Journal of Medicine (NEJM).

“These exciting data show that nirsevimab has the potential to offer RSV protection for all infants, which would be a paradigm shift in the approach to this disease,” said Principal Investigator and coauthor William Muller, MD, PhD, scientific director of clinical and community trials at Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago, and associate professor of pediatrics at Northwestern University Feinberg School of Medicine.

RSV is a common, contagious virus that causes seasonal epidemics of lower respiratory tract infections, leading to bronchiolitis and pneumonia in infants. It is also a leading cause of hospitalizations in all infants. The trial involved healthy term and late-preterm (gestational age at least 35 weeks) infants entering their first RSV season. Lurie Children’s Hospital was among the highest enrolling U.S. sites in the trial.

Nirsevimab is an investigational long-acting monoclonal antibody in development by AstraZeneca and Sanofi designed to protect all infants through their first RSV season with a single dose. Monoclonal antibodies do not require the activation of the immune system to help offer rapid and direct protection against disease.

Currently, the only available preventive option for RSV is palivizumab, which is limited to high-risk infants and provides 1-month protection, requiring five injections to cover an RSV season.

A separate phase II/III trial, also published in NEJM, which evaluated the safety of nirsevimab in infants with congenital heart disease, chronic lung disease, and prematurity entering their first RSV season, demonstrated that nirsevimab had a similar safety and tolerability profile compared with palivizumab. Results in this population of infants indicated similar protection against RSV to that in healthy term and late-preterm infants.

“We know that RSV has seen a resurgence with the easing of COVID-19 public health measures. This shows us a broad immunization approach is needed to help mitigate the substantial global burden RSV places on infants, their families, and healthcare services,” said Dr. Muller.


Study Sheds Light on COVID-19 Vaccine Effectiveness in 5- to 11-Year-Olds

Using data from 10 states, a study from the CDC is one of the first real-world studies to show that two doses of a messenger RNA (mRNA) vaccine provide protection against COVID-19–associated emergency department and urgent care visits among children aged 5 to 11 years.

The study also found that two doses of an mRNA vaccine provide protection against COVID-19–associated emergency department and urgent care visits as well as very high protection against hospitalization among adolescents aged 12 to 17 years.

“A positive pattern, similar to what we have reported in adults, is emerging,” said study coauthor Shaun Grannis, MD, MS, vice president for data and analytics at Regenstrief Institute and professor of family medicine at Indiana University School of Medicine. “Prevention of emergency department and urgent care visits shows that the vaccines are thwarting moderate COVID-19 in both children and adolescents; prevention of hospitalizations in 12- to 17-year-olds indicates vaccine effectiveness against more serious disease in this age group, which we hope to also see in 5- to 11-year-olds when there is sufficient data.

“We now have compelling evidence that vaccines and, for 16- and 17-year-olds, boosters provide important protection for both children and adolescents—data-driven information that parents should take into consideration when making decisions for their family,” said Dr. Grannis.

Vaccine and Antibody Effectiveness Blunted by Omicron Subvariants

Only one currently authorized antibody treatment retains its activity against all Omicron subvariants, according to new research by scientists at Columbia University and the University of Hong Kong. The study also shows that the effectiveness of mRNA vaccines is reduced against all three subvariants of Omicron.

The findings were published in Nature by David D. Ho, MD, director of the Aaron Diamond AIDS Research Center and the Clyde and Helen Wu professor of medicine at Columbia University Vagelos College of Physicians and Surgeons.

Omicron is a highly transmissible variant of SARS-CoV-2 that has caused the biggest surge in COVID cases so far in many countries. Researchers have identified three subvariants of Omicron that share 21 mutations in the spike protein and named them BA.1, BA.1.1, and BA.2.

When Omicron was first identified in November 2021, the dominant variant was BA.1. Since December, BA.1 cases have declined, while BA1.1 cases have risen and now make up around 40% of all Omicron cases sequenced globally. The BA.2 subvariant is increasing in prevalence.

In laboratory experiments, Dr. Ho and his team studied the ability of 19 monoclonal antibodies and the sera from individuals immunized with one of two available mRNA vaccines to neutralize the three known subvariants of Omicron.

Consistent with their previous study on the BA.1 variant, the researchers observed a similar loss of neutralization activity against BA.1.1 and BA.2 in blood samples from individuals who had received two mRNA shots. However, the decline in neutralization was less prominent in blood samples from individuals who had received three mRNA shots, reinforcing the importance of booster shots for sustaining immunity.

In neutralization experiments, all three variants exhibited a strong resistance to most of the monoclonal antibodies tested. Of 19 antibodies, 17 were ineffective against the BA.2 subvariant. The researchers found that bebtelovimab, the latest monoclonal antibody to receive FDA Emergency Use Authorization, is the only currently available antibody therapy that can adequately treat all three Omicron subvariants.

“The emergence of new variants is narrowing our treatment options and challenging the effectiveness of our current vaccines,” said Dr. Ho. “It is critical that we don’t relax prematurely and continue to devise novel strategies to contain this ever-evolving pathogen.”


Postvaccine Exercise Bumps Up Antibodies, Study Finds

Researchers at Iowa State University found that 90 minutes of mild-to-moderate–intensity exercise directly after a flu or COVID-19 vaccine may provide an extra immune boost.

In the newly published study, participants who cycled on a stationary bike or took a brisk walk for 1.5 hours after receiving a vaccine produced more antibodies in the following 4 weeks compared with participants who sat or continued with their daily routine post immunization.

The researchers found similar results when they ran an experiment with mice and treadmills.

“Our preliminary results are the first to demonstrate a specific amount of time can enhance the body’s antibody response to the Pfizer-BioNTech COVID-19 vaccine and two vaccines for influenza,” said kinesiology professor Marian Kohut, lead author of the paper published in the journal Brain, Behavior, and Immunity.

The researchers said the study’s findings could directly benefit people with a range of fitness levels. Nearly half of the participants in the experiment had a BMI in the overweight or obese category. During 90 minutes of exercise, they focused on maintaining a pace that kept their heart rate around 120 to 140 beats per minute rather than distance.

In the study, the researchers also tested whether participants could get the same bump in antibodies with just 45 minutes of exercise. They found the shorter workout did not increase the participants’ antibody levels. Dr. Kohut said the research team may test whether 60 minutes is enough to generate a response in a follow-up study.

As to why prolonged, mild-to-moderate–intensity exercise could improve the body’s immune response, Dr. Kohut said there may be multiple reasons. Working out increases blood and lymph flow, which helps circulate immune cells. As these cells move around the body, they are more likely to detect something that is foreign.

Data from the mouse experiment also suggested a type of protein (i.e., interferon alpha) produced during exercise helps generate virus-specific antibodies and T cells.

“But a lot more research is needed to answer the why and how. There are so many changes that take place when we exercise—metabolic, biochemical, neuroendocrine, circulatory. So, there’s probably a combination of factors that contribute to the antibody response we found in our study,” said Dr. Kohut.

The researchers are continuing to track the antibody response in the participants 6 months post immunization and have launched another study that focuses on exercise’s effects on people who receive booster shots.


HIV Vaccine Scientists Develop Immunogen That Produces Tier-2 Antibodies

Nearly 4 decades after its discovery, HIV has killed 36.3 million people, with no vaccine in sight. However, a new study by researchers at The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious diseases, and vaccine development, takes a promising step in the direction of developing an HIV vaccine.

The findings, published in Nature Communications, demonstrate the promise of using a unique, native-like trimer to develop Tier-2 neutralizing antibodies—the kind that matter for combating HIV—in mice for the first time.

Previously, eliciting these types of antibodies using candidate vaccines required long and expensive experiments in large animal models, creating a significant bottleneck on HIV-1 vaccine development. “With our new finding, we have opened the door to rapid, iterative vaccinology in a model that can produce Tier-2 neutralizing antibodies, enabling development of more advanced HIV vaccine concepts,” said Daniel Kulp, PhD, associate professor in the Vaccine & Immunotherapy Center at The Wistar Institute and corresponding author of the paper.

The researchers encoded the native-like trimer into DNA for delivery into the mice. This has the practical advantage of turning the host bodies into “antigen factories” instead of requiring what would otherwise be a complex vaccine-manufacturing process. The researchers then compared the results from the mice that received the DNA-encoded native-like trimer to results from mice that received a standard protein immunization. Only those mice that received the DNA-encoded native-like trimer developed Tier-2 neutralizing antibodies.

“We were able to generate strong immune responses with both platforms, but the DNA platform uniquely drove this neutralizing response,” said Dr. Kulp.

Once they verified that their immunization regimen was producing tier-2 antibodies, Dr. Kulp and his colleagues isolated monoclonal antibodies from the mice and used cryo-electron microscopy to determine the atomic structure of one Tier-2 neutralizing monoclonal antibody. They found that the antibody binds to an epitope (a segment of a protein that sticks out of the antigen, which prompts an immune response) called C3V5. In the gold standard HIV vaccine model (nonhuman primates), prior research has shown that antibodies binding to C3V5 protect animals from a SHIV infection, which is a close relative of HIV that infects nonhuman primates.

“The structure gives us incredible insight into how this antibody is able to neutralize the virus,” said Dr. Kulp. “For the first time, we can strategize about how to design new vaccines that can generate broadly neutralizing antibody responses to the C3V5 epitope.”

Coauthor David B. Weiner, PhD, executive vice president and director of the Vaccine & Immunotherapy Center and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute, emphasized the utility of their findings.

“What we’ve done is enable direct in vivo self-assembly of structurally designed immunogens, which are engineered and delivered using nucleic acid technology, inside the vaccinated animal. Our data demonstrating induction of autologous Tier-2 neutralization illustrate the value of this approach as a tool to create surgically tailored immunity against a difficult pathogen’s vulnerable sites, in this case for HIV.”


COVID-19 Vaccination Also Boosts Mental Health, Study Finds

Receiving a vaccine for COVID-19 measurably improved the psychological well-being of participants in the Understanding Coronavirus in America study, a large, longitudinal look at the impact of the pandemic on individuals in the United States. Vaccination was associated with declines in distress and perceived risks of infection, hospitalization, and death. The study, appearing in the American Journal of Preventive Medicine, validates the intuitive but previously unanswered questions of whether becoming vaccinated reduces perceived risks associated with COVID-19 and whether the reduction of these fears leads to improvements in mental health and quality of life.

“Our study documents important psychological benefits of vaccination beyond reducing the risk of severe illness and death associated with COVID-19,” said lead investigator Jonathan Koltai, PhD, Department of Sociology, University of New Hampshire, Durham.

Psychological distress and anxiety increased sharply across the population following the onset of the COVID-19 pandemic. Several factors contributed, such as widespread job and income loss, food insecurity, social isolation, caregiving burdens, substance abuse, and racialized discrimination. Depressive symptoms persisted and increased into 2021 for those experiencing an accumulation of stress exposures. Not surprisingly, many individuals are also experiencing anticipatory fears that contribute to rising mental health problems.

Data from a nationally representative study of 8,090 adults who were interviewed regularly between March 2020 and June 2021 revealed declines in COVID-related risk perceptions and psychological distress following vaccination. Specifically, adults who received at least one dose of the COVID-19 vaccine between December 2020 and June 2021 reported a 7% relative reduction in mental distress measured using the Patient Health Questionnaire 4 distress scores from average levels in the survey period immediately prior to vaccination.

Reductions in distress were partially explained by declining risk perceptions following vaccination. Becoming vaccinated was associated with a 7.77 percentage point decline in perceived risk of infection, a 6.91 percentage point decline in perceived risk of hospitalization, and a 4.68 percentage point decline in perceived risk of death. Adjusting for risk perceptions decreased the vaccination-distress association by 25%.

These effects persisted and became stronger up to at least 8 weeks following vaccination. It is noteworthy that while responses from vaccinated and never-vaccinated participants followed similar trends prevaccination, they significantly diverged following vaccination. Becoming vaccinated made people feel safer in addition to being safer.

The impact of vaccination on mental health varied by race/ethnicity. The largest reductions in distress were observed among American Indians and Alaska Native individuals, who have suffered disproportionately from COVID-19. The breakout among racial/ethnic groups was proportional to the overall U.S. population during the study period, with the highest rates of vaccination observed among Asian and Pacific Islanders and the lowest rates of vaccination observed among Black participants.

With the rapid rise of the Omicron variant in late 2021 and early 2022, urgent measures are needed to increase vaccination rates and achieve vaccine equity, both locally and globally. These efforts need to be coupled with effective communication about the benefits, both physical and mental, associated with vaccination.

Dr. Koltai stressed, “To ensure these benefits are widely shared, efforts to increase vaccination and booster rates in early 2022 need to prioritize equitable distribution and access to vaccines.”


Study Shows Waning Effectiveness of Third mRNA Vaccine Doses

A nationwide study from the CDC is the first to show that immunity against severe COVID-19 disease begins to lessen 4 months after receipt of the third dose of an mRNA vaccine (Pfizer or Moderna). Waning immunity was observed during both the Delta and Omicron variant waves in similar fashion to how mRNA vaccine effectiveness wanes after a second dose. Although protection decreased with time, a third dose was still highly effective at preventing severe illness with COVID-19.

Until this study, little was known about durability of protection following three doses, especially during periods of Delta or Omicron predominance in the United States.

“The mRNA vaccines, including the booster shot, are very effective, but effectiveness declines over time. Our findings suggest that additional doses may be necessary to maintain protection against COVID-19, especially for high-risk populations,” said study coauthor Brian Dixon, PhD, MPA, Regenstrief Institute and Indiana University Richard M. Fairbanks School of Public Health director of public health informatics. “We also found that people who are Hispanic or Black are half as likely to have a third vaccine dose than people who are White, making people who are Hispanic or Black more vulnerable to severe COVID and highlighting the need for public health officials to double down on efforts to protect these vulnerable populations.”

According to a CDC dashboard, as of February 8, 2022, among Americans aged 65 years or older who received a booster dose: 72.3% were people who are White, 8.9% were Hispanic, and 7.6% were Black. The rates among people who are Black or Hispanic are lower than the proportion of those groups with two doses, and these proportions are lower than the percentage of the U.S. population composed of people from those groups, indicating disparities in who has received third doses in the U.S.

In a recent 2-week period, however, higher rates of vaccination have been observed among these minority groups (16.9% of recent boosters are among people who are Hispanic; 12.7% of recent boosters are among people who are Black). In the study, among patients who are White in the emergency department/urgent care (ED/UC), 12% had received a third dose compared with 7% of patients who are Hispanic and 6% of patients who are Black. Similar disparities in third-dose administration were observed among those patients hospitalized for severe COVID-19.

Overall, the study reported that individuals with second and third doses of an mRNA vaccine had greater protection against hospitalizations (severe disease) than against ED/UC visits (symptoms which may not require hospitalization). Vaccine effectiveness was also lower overall during the Omicron period than during the Delta period.

Vaccine effectiveness against ED/UC visits declined from 97% within the first 2 months of receiving a booster to 89% effectiveness at 4 months or longer during the Delta-predominant period (summer/early fall 2021). During the Omicron-predominant period (late fall 2021/winter 2021-22), vaccine effectiveness against ED/UC visits was 87% during the first 2 months after a third dose, decreasing to 66% at 4 months after a third dose.

After the third dose, protection against Delta variant–associated hospitalization declined from 96% within 2 months to 76% after 4 or more months. Vaccine effectiveness against Omicron variant–associated hospitalizations was 91% during the first 2 months, declining to 78% at 4 months.

“Our findings confirm the importance of receiving a third dose of mRNA COVID-19 vaccine to prevent moderate-to-severe COVID-19 illness, especially among those with comorbidities,” said study coauthor Shaun Grannis, MD, MS, vice president for data and analytics at Regenstrief Institute and professor of family medicine at Indiana University School of Medicine. “That protection conferred by mRNA vaccines waned in the months following a third vaccine dose supports further consideration of booster doses to sustain protection against moderate-to-severe COVID-19 illness.”

“Waning 2-dose and 3-dose Effectiveness of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance—VISION Network, 10 States, August 2021–January 2022” was published in the CDC’s Morbidity and Mortality Weekly Report.

Repeated Seasonal Vaccines Better Protect Children Against Future Flu Pandemics

Researchers at McMaster University have found that children who receive years of season-specific influenza vaccines develop antibodies that also provide broader protection against new strains, including those capable of causing pandemics. The same ability, the scientists found, does not exist in adults.

The findings, reported in Cell Reports Medicine, could inform the design of a universal influenza virus vaccine for children, who are especially vulnerable to serious complications from flu, such as pneumonia, dehydration, and in rare cases, death.

“Little is known about how seasonal flu vaccination impacts the immune responses in children, who are a major source of flu transmission and a very-high-risk group,” explained Matthew Miller, lead author of the study and associate professor at the Michael G. DeGroote Institute for Infectious Diseases Research. “Understanding how seasonal vaccination and different vaccine formulations shape childhood immunity is critical for effective prevention.”

Children and adults are fundamentally different in their immune responses to influenza virus, Dr. Miller added, whose laboratory is part of McMaster’s Global Nexus for Pandemics and Biological Threats. Unlike small children, most adults have been infected with and vaccinated against flu many times throughout their lives.

“When we give adults vaccines, they make a very specific immune response against seasonal strains,” he says. “Adults simply don’t generate immune responses to seasonal flu vaccines capable of protecting them from pandemic viruses like children can.”

The researchers spent 3 years studying immune responses in children aged 6 months to 17 years. They found that as the children grew older, they became less capable of producing broadly protective antibodies because of their repeated exposure to influenza, through infection or vaccination.

While COVID-19–related measures such as distancing and masking have also resulted in lower rates of influenza, Dr. Miller warns the flu will return, possibly in dangerous forms.

Influenza has caused five pandemics in the past 100 years. The Spanish Flu of 1918-1919 killed roughly 50 million people worldwide at a time when the global population was about 1.8 billion—less than a quarter what it is today.

For the study, researchers also compared two forms of vaccine: the conventional flu shot and a nasal spray vaccine that works in the upper respiratory tract, where infection first takes hold.

Both worked equally well at generating broadly protective antibodies, which is welcome news for parents seeking a painless alternative to needles.

“This is an important finding because it means we have flexibility in terms of the type of vaccines we can use to make a universal vaccine for children. We now know that children’s immune systems are much more flexible than adults’ when it comes to being able to teach them how to make these broadly protective responses,” says Dr. Miller.

Intranasal Flu Vaccine With Nanoparticles Offers Robust Protection

An influenza vaccine administered through the nose and constructed with nanoparticles that enhance immune response offers strong protection against different influenza virus strains, according to researchers in the Institute for Biomedical Sciences at Georgia State University.

The intranasal vaccine contributed to multifaceted immune responses, leading to robust cross protection against influenza in mice. The vaccine consists of PEI-HA/CpG nanoparticles. PEI (polyethyleneimine), a robust and versatile delivery system, can simultaneously carry antigens (hemagglutinin, HA) that induce an immune response in the body and adjuvants (CpG) that enhance the body’s immune response to an antigen for optimal immunoenhancement.

These comprehensive immune responses and cross protection were long lasting, exhibiting defense from influenza virus over 6 months after immunization. The findings are published in ACS Applied Materials & Interfaces.

Intranasal vaccination is an ideal approach for infectious respiratory diseases such as influenza. Seasonal influenza vaccines generally induce narrow immune responses that rapidly decline, which leaves populations vulnerable to novel influenza strains. Advancements in influenza vaccine technology are needed to protect against a wide range of influenza viruses. Intranasal vaccination can improve local mucosal immune responses by preventing influenza infection at the portal of virus entry.

In the influenza virus, HA is a protein that plays a crucial role in the early stages of virus infection. Influenza HA has a head region and stalk region. Current influenza vaccines elicit immune responses against the HA head, but this region is highly changeable and accounts for lowered efficiency against different strains. The HA stalk region is more conservative across different strains of influenza viruses.

Protein antigens that are administered intranasally are usually less able to provoke an immune response, so adjuvants are needed to have highly efficient intranasal vaccines. Adjuvants, such as CpG, can enhance and manipulate immune responses, thus improving the potency and breadth of protection.

“The PEI-HA/CpG nanoparticles show good potential as a cross-protective influenza vaccine candidate,” said Baozhong Wang, corresponding author of the study and a professor in the Institute for Biomedical Sciences at Georgia State. “The combination of PEI and CpG in the PEI-HA/CpG nanoparticle group contributed to the multifaceted immune responses, leading to vigorous cross protection. The incorporation of CpG and antigens into the same nanoparticle enhanced cellular immune responses.

“Our results revealed that the nanoparticles significantly enhanced HA immunogenicity, or the ability to provoke an immune response, providing cross protection against different influenza virus strains. The conserved HA stalk region induced substantial antibodies in the nanoparticle immunization groups,” said Dr. Wang.

“Nanoparticle platforms have shown intriguing characteristics and great potentialzs in the development of next-generation cross-protective influenza vaccines,” said Chunhong Dong, the first author of the study and a postdoctoral fellow in the Institute for Biomedical Sciences. “However,” he added, “challenges exist to the successful research and development of nanoparticle vaccines. Though no apparent adverse effects were observed in the study, a more comprehensive safety evaluation of the nanoparticle adjuvant system is needed before clinical trials.”

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