September 22, 2023

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New RSV drugs are expected to protect all babies from the most threatening respiratory virus

New RSV drugs are expected to protect all babies from the most threatening respiratory virus

New RSV drugs are expected to protect all babies from the most threatening respiratory virus.

FDA approved long-acting antibody, Europe and the United States are expected to protect all babies from the most threatening respiratory virus.

Respiratory syncytial virus (RSV) is a very unfamiliar name to many people. But RSV is extremely “familiar” to our bodies-almost everyone cannot avoid being infected by RSV, and they are repeatedly infected throughout their lives.

Most RSV infections are not dangerous and present as mild upper respiratory infections, but RSV can also cause serious and even life-threatening lower respiratory infections.

Severe RSV infections are mostly concentrated in people with weaker physical functions and imperfect immune systems, such as infants and the elderly.

Infants are the group most threatened by RSV .A study estimated that in 2015 alone, there were 33.1 million cases of RSV lower respiratory tract infection in infants and young children under the age of 5 worldwide, resulting in 3.2 million hospitalizations and nearly 60,000 deaths.

Of these, infants less than 6 months of age accounted for 1.4 million hospitalizations and more than 27,000 deaths [1].

It is not an exaggeration to say that RSV is the respiratory virus that poses the greatest threat to infants and young children. Unfortunately, there has been neither targeted treatment nor good preventive measures for RSV infection for many years, and the related disease burden has not improved for a long time.

However, in recent years, advances in antibody and vaccine design have completely subverted the field of RSV, making it the hottest battlefield for new drugs .

Pfizer and GSK each have a vaccine approved by the FDA, and Moderna ‘s RSV mRNA vaccine is also applying for marketing .

In addition to the intense RSV vaccine war, the use of antibodies for passive immune protection is also one of the research and development directions of RSV drugs.

On November 4, 2022, after the EU approved the marketing of the long-acting RSV prophylactic monoclonal antibody Beyfortus (nirsevimab) , on July 17, 2023, the FDA also approved the antibody’s application for marketing in the United States. If nothing else, the CDC will establish Beyfortus’ end-use scenario in August. Today we will introduce RSV and nirsevimab.

Like the European Union, the FDA also approved the use of Beyfortus in all infants, which means that during the peak period of RSV in autumn and winter this year, as the drug is officially put into use, it will be possible to prevent RSV infection for all infants .

RSV: The invisible killer

RSV can be said to be “hidden in the city”. It was only discovered by scientists in 1956, and it was found in chimpanzees, and it was not regarded as a pathogen that can infect humans [2].

The next year, another group of scientists found the same virus in children’s respiratory tract infections, and later found that the virus infection was extremely common in infants and young children through antibody analysis[3].

This belatedly discovered virus was later named Human Respiratory Syncytial Virus -hRSV. The chimpanzees who were first found to be infected with RSV were actually infected by keepers.

Even when RSV was discovered, there was a lack of understanding of its actual threat for a long time.

RSV infection is so common that 95% of infants under the age of 2 have been infected with RSV.

After an initial infection, a person can also be reinfected with RSV throughout life. The vast majority of infections are not serious, limited to the upper respiratory tract, and symptoms are no different from the common cold [4].

However, with the progress of the epidemiological investigation of RSV, the not “mild” side of this virus has become increasingly clear.

15-50% of RSV infections in infants and young children will affect the lower respiratory tract.

Different from the milder upper respiratory tract infection, viral infection is more dangerous when it spreads to the lower respiratory tract, which may cause bronchiolitis, pharyngotracheobronchitis and even viral pneumonia .

Among them, bronchiolitis has almost become a classic manifestation of RSV infection, and about 70% of them are caused by it.

Ultimately 1-3% of RSV-infected infants require hospitalization, and 5-10% of hospitalized infants are severe enough to require admission to the intensive care unit (ICU) [5].

Since the first infection of many infants occurs shortly after birth, the immune system is not fully developed, so the overall disease burden of RSV cannot be underestimated.

In 2015 alone, an estimated 33.1 million cases of lower respiratory tract infection caused by RSV occurred in children under 5 years of age worldwide, resulting in 3.2 million hospitalizations and nearly 60,000 infant deaths [1].

RSV, which seems to have a very low presence, has actually been the number one factor in the hospitalization of respiratory tract infections in infants and young children .

In developed countries, RSV is the number one factor in all hospitalizations of children under the age of 5 [6].

The threat of RSV to infants knows no borders. Due to limited medical conditions in developing countries, RSV infection is still one of the most important factors of neonatal death [7].

Several studies in China have also shown the extremely serious disease burden of RSV.

Antibody testing carried out in Beijing ten years ago found that the RSV infection rate was as high as 71% in infants under 6 months old, and 89% in 1-3 years old[8].

And a study of acute lower respiratory tract infection caused by RSV among young children in 58 countries in 2019, the number of hospitalizations for acute lower respiratory tract infection caused by RSV in children under 5 years old in China accounted for 18-27% of the global total, which means 2,500 children every day Hospitalization for RSV infection kills up to 7,400 young children a year [9].

A step-by-step search for drugs against RSV

RSV is one of the respiratory infectious diseases with the greatest global health burden. However, in the 1960s, the development of the first-generation RSV vaccine failed, and infants and young children even died in clinical trials.

 How to provide protection for infants and young children who are most threatened by RSV has become a problem that has plagued the medical community for a long time.

In the 1970s and 1980s, scientists discovered that the infusion of immunoglobulin can provide passive immunity for infants and young children, preventing bacterial and viral infections.

For RSV, passive immunization with immunoglobulins with higher titers of neutralizing antibodies (antibodies that can specifically block virus entry into cells) can also prevent RSV-induced pneumonia in animal models.

A series of studies eventually led to the US FDA’s approval of RespiGam in 1995 for RSV prophylaxis in high-risk neonates under two years of age.

RespiGam is an immunoglobulin containing high-titer RSV neutralizing antibodies——RSV-IVIG, which is a mixture of various antibodies [10].

Immunoglobulin is inconvenient to prepare and use, and it is difficult to popularize.

Until 1998, palivizumab, the first monoclonal antibody specifically for RSV prevention, was approved for marketing in the United States.

Palivizumab can bind to the F protein of RSV, which is one of the key proteins for RSV to enter human cells.

The affinity of palivizumab to the F protein is very good, which is reflected in the strong neutralization ability of the antibody against RSV virus.

In two phase III clinical trials of high-risk neonates, palivizumab reduced the risk of hospitalization for RSV infection by 55% and 45%, respectively [11].

While palivizumab is effective for prevention, it requires monthly injections during the up to 5-month RSV peak season .

This is why the use of palivizumab in developed countries such as Europe, America, Canada, and Japan has been approved for nearly 25 years, and they are all limited to premature babies, or those with bronchial dysplasia, and congenital heart disease.

These infants with the highest risk of severe RSV are used as protection. Most infants and young children remain unprotected from RSV [12].

Although high-risk infants, such as those born prematurely, are at higher risk for severe RSV disease, the risk is not negligible for infants without any underlying health problems.

Even because of the larger base, ordinary healthy infants accounted for the absolute majority of infants hospitalized due to RSV infection.

Statistics from the United States show that 85% of infants under the age of two who are hospitalized due to RSV infection do not have any underlying health problems [13].

New goal: protect all babies

Because RSV infection is very common, in fact 2-3% of infants will be hospitalized due to RSV infection.

Regardless of the month of birth, the main reason for hospitalization in infancy is RSV infection [14].

Therefore, unless better interventions are provided for all infants, RSV will continue to be an invisible killer during the most vulnerable period of infants and young children.

In addition, even in places with better medical conditions, infants and young children infected with RSV and eventually died are relatively rare, but severe RSV infection also has long-term risks for children. For example, severe RSV infection in infants and young children increases the risk of asthma [15].

Palivizumab undoubtedly proves that the monoclonal antibody that neutralizes the RSV virus is the right path, but the half-life of palivizumab in the body is only 20 days. In order to maintain the drug concentration in the body at a level that can effectively prevent RSV, it can only be re-injected every month.

In addition, the principle of monoclonal antibody drugs to prevent RSV is that neutralizing antibodies block the virus from invading cells.

The neutralizing ability of different neutralizing antibodies is different, which will correspond to the difference in effectiveness.

It can be inferred that if a monoclonal antibody with stronger neutralizing ability and longer half-life can be found, it is entirely possible to maintain a better RSV infection prevention effect with fewer medications.

This more effective and more convenient drug is expected to be promoted in all infants and protect all infants from the threat of RSV.

This hope is about to become a reality with the emergence of a new generation of RSV monoclonal antibody nirsevimab .

Nirsevimab also binds to the F protein of the RSV virus to block the virus from invading human cells.

However, its specific binding site is different from that of palivizumab, which can just hit the state before the F protein binds to human cells, that is, the pre-fusion conformation.

The pre-fusion conformation is the most “fragile” moment of the RSV virus, and the neutralizing antibody against RSV in this state has the highest neutralization efficiency [16].

In vitro experiments, the ability of nirsevimab and RSV virus is more than 50 times higher than palivizumab [17].

New RSV drugs are expected to protect all babies from the most threatening respiratory virus.

Figure. The binding site of nirsevimab is in the prefusion conformation of RSV virus F protein (Prefusion RSV F), which has better neutralizing ability (Source: CDC ACIP in June 2022)

In addition to stronger neutralizing ability, nirsevimab also introduces three amino acid mutations in the Fc domain of the antibody—the YTE mutation.

The Fc domain of an antibody is closely related to the function and half-life of the antibody. The YTE mutation can greatly extend the half-life of the antibody in the human body, and the half-life of nirsevimab can reach about 60-70 days [17].

Such a long half-life means that one injection of nirsevimab can maintain the antibody concentration in the body at a level of high-efficiency protection against RSV infection within 5 months, so that one injection can deal with the entire season of high incidence of RSV .

The advantages of “performance indicators” make nirsevimab have the potential to become a powerful tool for preventing RSV in all infants, but the more critical thing is whether it can prove itself in rigorous clinical trials. To this end, nirsevimab launched two pivotal clinical trials.

One was a phase II trial in preterm infants of less than 35 weeks’ gestation, in the same population as palivizumab [18].

Another phase III clinical trial, code-named Melody, highlights the real ambition of nirsevimab-in healthy full-term or near-term infants, the purpose is to prove that nirsevimab can protect against RSV for ordinary infants, not limited to high-risk infants[19 ].

In addition to the difference in the recruited population, the above two studies are very similar in design.

Both record the lower respiratory tract infection caused by RSV within 5 months after an intramuscular injection of nirsevimab or placebo to see whether nirsevimab reduces the risk.

In July 2020, the results of the phase II clinical trial of nirsevimab in premature infants were first announced and published in the New England Journal of Medicine.

The trial eventually recruited about 1,500 premature babies born between 29 and 35 weeks of gestation, about 1,000 of whom were injected with nirsevimab and about 500 were given saline as a placebo group.

The results showed that within a 5-month follow-up period, nirsevimab reduced the risk of lower respiratory tract infection caused by RSV by 70.1%, achieving a single dose of protection against the entire season of RSV infection [18].

In March 2022, the results of the first group of subjects in the much-anticipated Melody trial were also published in the New England Journal of Medicine.

The published trial results also came from nearly 1,500 babies, all of whom were older than 35 weeks’ gestation and did not meet the criteria for preterm birth that had previously been used with palivizumab.

About 1,000 infants were given a single dose of nirsevimab, and about 500 others were given saline.

One injection of nirsevimab reduced the risk of lower respiratory tract infection caused by RSV by 74.5%, and the effectiveness was highly consistent with the results in premature infants [19].

The results of these two key clinical trials not only showed that one injection of nirsevimab in high-risk infants could replace palivizumab, which had to be injected again every month, but also proved for the first time in healthy infants that infusion of monoclonal antibodies for passive immunization can be highly effective. Prevent RSV infection .

New RSV drugs are expected to protect all babies from the most threatening respiratory virus.

Figure. One dose of nirs evim ab maintained good RSV protection for 5 months (Image source: Citation 19)

Effectiveness is one aspect of a drug, and another extremely important aspect is safety, especially if the target population of the drug is wider, the requirements for safety will be higher.

RSV prevention drugs that are promoted to all infants must have an excellent safety profile.

Analyzing the safety of nirsevimab in multiple clinical trials, it will be found that the incidence of adverse reactions is the same as that of normal saline as a placebo .

In other words, nirsevimab is not only effective, but also safe.

In addition to effectiveness and safety, if the target population of nirsevimab is extended to all infants, another issue worthy of attention from the perspective of public health decision-making is the “efficiency” of treatment.

From an ethical and emotional point of view, we naturally believe that everyone’s life is precious, but when it comes to issues such as public health decision-making and medical resource allocation, we must also consider how much it costs to save a life, such as conversion How many people are vaccinated with a certain vaccine can reduce the hospitalization of a related infectious disease.

It is estimated from the results of the Melody trial that the use of nirsevimab in only 11 infants can reduce a lower respiratory tract infection, and 57 infants can avoid hospitalization caused by a respiratory tract infection. This protective efficiency is no different from that of many childhood vaccines [19 ].

Nirsevimab can not only help infants protect against RSV risk for a season with one injection, but also achieve “economical” efficiency from the perspective of public health.

The RSV protection that is about to usher in a revolutionary breakthrough

In addition to nirsevimab, the RSV vaccine has also achieved a breakthrough, and soon we will have more effective tools to deal with RSV than ever before .

RSV high-risk groups are concentrated at both ends of the age – infants and the elderly. Almost all people will be repeatedly infected with RSV in their lives, and the arrival of the high season of RSV will also lead to the possibility of a run on the medical system.

To reduce the health burden of RSV on society as a whole, the elderly need to be vaccinated against RSV every year like the flu.

The RSV vaccines of Pfizer and GSK, which have also been approved by the FDA, have shown extremely positive effectiveness in the elderly.

In phase III clinical trials, they have shown that they can reduce the risk of lower respiratory tract infection caused by RSV by 60-80% [21].

Administration of the RSV vaccine is more complicated for infants. Many babies will face RSV shortly after birth, when their immune system is not yet perfect, and it is difficult to achieve perfect protection through direct vaccination. Pfizer’s RSV vaccine has also been approved for use in pregnant women.

The plan is to inoculate RSV vaccine in the second and third trimesters of pregnancy.

The antibodies produced by the mother pass through the placenta into the fetus to protect the newborn.

But there is considerable uncertainty about issues such as the willingness of pregnant women to be vaccinated.

Moreover, antibody transfer mainly occurs in the third trimester of pregnancy, and premature infants cannot obtain sufficient protection.

Therefore, nirsevimab will remain a very important protective measure for newborns.

In addition, from the perspective of public health, nirsevimab, a passive immune drug that can obtain high-efficiency protection immediately after use, is also an extremely important supplement compared to vaccines that do not take effect until 1-2 weeks after vaccination.

In the past, the RSV epidemic seasons were all in autumn and winter.

For example, the peak of RSV detection in the United States from 2016 to 19 was from December to January.

However, possibly affected by the COVID-19 epidemic, there will be an abnormal peak of RSV infection in August 2021, and there will be an early peak in October in 2022.

It is also easier to deal with the abnormal epidemic performance of the virus with nirsevimab, which has a flexible time and immediate effect .

Only the combination of active immunization with RSV vaccine and passive immunization with nirsevimab can effectively control the threat of RSV.

This article, adapted from an article written when nirsevimab was approved in Europe in November 2022, focuses on the RSV threat in infants and the history of RSV antibody development.

Compared with nirsevimab among the RSV antibodies, the competition for RSV vaccines is more intense. This fall, the United States will usher in the duo competition between Pfizer and GSK.

Moderna also submitted a marketing application to the FDA in July.

Regarding the threat of RSV among the elderly and the vaccine war, I will write another article, welcome to pay attention.

References (swipe to browse)

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New RSV drugs are expected to protect all babies from the most threatening respiratory virus.

(source:internet, reference only)

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