Jared Kaltwasser

Previously infected people who are vaccinated have the strongest protection against reinfection with SARS-CoV-2, according to a new study, but the data also show that protection from vaccination and natural infection wanes significantly over time.

, helps quantify the benefits of natural immunity and vaccination

It has long been known that natural immunity from severe acute respiratory syndrome wanes over time, and that vaccines against SARS-CoV-2 require 

 and may be less effective against new strains of the virus, though they appear to continue to provide robust protection against severe disease.

What is less clear, according to corresponding author Yair Goldberg, PhD, of the Technion-Israel Institute of Technology, and colleagues, is how protection conferred by the combination of natural immunity and vaccination changes over time.

The investigators decided to use data from the Israeli Health Ministry’s databases to track immunity over time among groups with different immunity statuses. The groups included unvaccinated people with a history of infection, vaccinated people with a history of infection, and vaccinated people who had no history of infection (and thus no natural immunity). The authors used data from August and September 2021, a period of time when the delta SARS-CoV-2 variant was predominant in Israel.

Data from more than 5.7 million people was included in the study. Infection risk was translated into rates of infection per 100,000 person-days, adjusted for confounding variables. The vaccine used in the analysis was the Pfizer/BioNTech mRNA vaccine.

The data showed a waning over time in all protection categories, but it differed based on infection history and vaccination status. Unvaccinated people with a history of infection were re-infected at a rate of 10.5 cases per 100,000 person-days 4-6 months following their initial infection. Over time, however, their natural immunity waned. Among unvaccinated people whose first infection was at least a year earlier, the rate of infection was 30.2 cases per 100,000 person-days.

Rates were considerably lower among people with a history of infection who had received a single vaccine dose. For them, the rate of reinfection was just 3.7 cases per 100,000 person-days within the first 2 months following vaccination. Once 6 months had passed following vaccination, the rate rose to 11.6 cases per 100,000 person-days.

Lastly, among people with no history of infection but who had received 2 vaccine doses, case rates in the first 2 months following vaccination were 21.1 per 100,000 person-days. After the 6-month post-vaccination mark, case rates jumped to 88.9 cases per 100,000 person-days.

“In findings that were consistent with those of other studies, after several months, persons with hybrid immunity were better protected against reinfection than uninfected persons who had previously received two doses of vaccine (the two-dose cohort,” Goldberg and colleagues wrote. “Furthermore, we found that a single dose of the vaccine administered to a previously infected person or a booster dose administered to an uninfected person who had received two doses of vaccine restored the level of protection to the level in the early months after recovery or vaccination.”

Though their study found clear benefits to vaccination, the authors noted that such data is inherently confounded by changes to the SARS-CoV-2 virus itself; the data here may not necessarily apply the same way to future variants, they noted.

The authors also noted that their data are based on cases confirmed by PCR testing. At the time, the Israeli government’s policy called for mandatory PCR testing for all people who came in contact with an infected person. However, they said the rate of PCR testing tended to be lower in patients who had recovered from infection but were unvaccinated, and thus it is possible the study over-estimated the level of protection in that cohort.

Still, the investigators said the data tell a story both about the protection conferred by infection and vaccination, one that should be heeded by 

policymakers as they consider future vaccination policies

“An understanding of the rates of waning immunity after immunity-conferring events is important for policy making regarding the need for and the timing of additional vaccine doses,” they concluded.

Goldberg Y, Mandel M, Bar-On YM, et al. Protection and Waning of Natural and Hybrid Immunity to SARS-CoV-2. 

. 2022;386(23):2201-2212. doi:10.1056/NEJMoa2118946

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Patients with a history of infection who were also vaccinated had the strongest protection, the data showed.

Against COVID-19, Both Natural and Vaccination-Mediated Protection Wane Over Time

Just as “COVID-19” became a household term when it was designated as the name of the disease caused by SARS-CoV-2, terms like “Delta variant” and “omicron variant” have since become buzzwords, hearkening variations in the virus and new waves of infections.

Yet, even as countries and local jurisdictions have adopted, rolled-back, and re-implemented public health measures to adapt to changing infection rates and scientific evidence, one thing has not yet changed—the composition of the COVID-19 vaccines.

As healthcare providers and public health officials continue to 

, many are wondering whether and when an updated vaccine will be necessary.

Hana M. El Sahly, MD, a professor at the Baylor College of Medicine, told 

 that the good news is that the current vaccines have held up well.

“The current vaccines continue to provide significant protection against severe disease caused by all the variants that have emerged to date,” El Sahly, who chairs the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC), said.

In March, the Centers for Disease Control and Prevention (CDC) reported that, while hospitalizations were up across the board due to omicron, adults who were unvaccinated were 

 to be hospitalized than people who were 

, Pfizer CEO Albert Bourla, PhD, and other pharmaceutical industry executives discussed the potential for updated vaccines. Bourla said his company has the capability to quickly develop vaccines that would be effective against particular variants, but he said that is not necessarily the goal.

“It’s easy to do something only against omicron,” he said. “What scientifically and technically is more challenging…is to be effective against everything known so far, so we don’t have different vaccines for different variants.”

He said investigators at his company are currently trying to figure out the most effective path forward, after which they will make an application to the FDA and European Medicines Agency to produce an updated vaccine.

El Sahly said it is reasonable to expect that a vaccine designed to stop omicron infections would have higher antibodies against omicron and its related variants.

“But the question would be: what would the incremental benefit be at a population level in terms of prevention of COVID-19 deaths and critical disease?” she said.

More and more people in the United States and elsewhere have been vaccinated, infected, or both, and she noted that data from the US, United Kingdom, and South Africa suggests that background population immunity is lowering morbidity and mortality rates from COVID-19.

“Whether a new variant emerges that can escape this background immunity and that of a new vaccine that uses current variants is unknown,” she said.

Journal of the American Medical Association, 

FDA Commissioner Robert Califf, MD, and colleagues wrote that COVID-19 will likely “circulate globally for the foreseeable future,” and that vaccination efforts would likely transition to a model similar to the flu vaccine, which is updated annually. They said officials will need to make decisions this summer about who should receive additional vaccine boosters, and about the composition of the vaccine for the 2022-2023 COVID-19 “season.”

“In the event of a major fall or winter wave, a vaccine with optimal variant coverage might facilitate significant reductions in lost productivity and healthcare utilization from both acute and chronic complications of COVID-19, including postacute COVID-19 syndrome,” they wrote.

 that physicians with anxious patients should help by providing context.

“I would tell the physician if someone received 3 doses of vaccines, then the likelihood of severe disease is extremely low unless [the patient is] immunocompromised or frail,” she said. “Also, a previous infection is a ‘boost’ of sorts to our 2/3/4 doses of vaccines previously received, and this information should be shared to help with the anxiety of some patients.”

She said it is important that patients—and healthcare professionals—understand that the goal of the vaccine is not so much to prevent all infections with SARS-CoV-2 and its variants, something she said is not likely an achievable goal with current technology. Instead, she said, the goal is to limit its consequences.

“From a clinical and public health standpoint the goal is preventing critical illness and death,” she said. “It is important to set the expectations as such.”

Rather than developing vaccines for each new variant, some officials are pushing to follow the flu vaccine model, with annual vaccination.

As Omicron Spreads, Public Health Officials Ponder When to Update COVID-19 Vaccine

Ferring Pharmaceuticals’ investigational 

 infection (CDI) therapy delays recurrence in patients with a history of repeat infections, according to newly released data.

American Gastroenterological Association’s Digestive Disease Week 2022

, which was held in San Diego. The report showed that RBX2660, an investigational microbiota-based live biotherapeutic, led to lower rates of recurrence among patients treated with standard-of-care antibiotics followed by RBX2660, compared to those treated with antibiotics followed by placebo. However, it also showed that time to recurrence among those who recurred was more than twice as long in patients who were given the therapeutic rather than placebo.

Paul Feuerstadt, MD, of PACT Gastroenterology Center, in Connecticut, explained that the new findings are based on data from the PUNCH CD3 trial, a placebo-controlled phase 3 trial testing RBX2660 in patients with documented recurrent CDI who had already undergone standard antibiotic treatment.

“Within that abstract, they looked at 262 patients enrolled in the PUNCH CD3 trial, and they drew a Kaplan-Meier curve for time to recurrence,” explained Feuerstadt, who has studied RBX2660 but was not an author of the time-to-recurrence study. “The time to recurrence in the placebo arm, the median 25th percentile, was 14 days versus 30 days in the RBX2660 arm.”

Feuerstadt said the findings are significant for a couple of reasons. First, they give insights into the timing of recurrences. He said most of the existing scientific evidence suggests that recurrences are most likely to happen within the first month. The new data support that timeline. However, Feuerstadt said the study also shows the impact of RBX2660 on recipients’ metabolisms.

“What that tells me is that progress was made,” he said. “The metabolic environment did have progress.”

Feuerstadt said the study affirms that the intervention of RBX2660 led to improvements in patients’ metabolic milieu which in turn lowered the patients’ susceptibility to recurrence.

“In the placebo environment, that milieu wasn't created or wasn't fortified,” he said. “Therefore, the time to recurrence was shorter, whereas the time to recurrence in the RBX2660 arm was almost two weeks longer, meaning that the environment was created, but it might not have been enough to sustain the effect.”

The study data included 8 weeks of follow-up, by which time 32 of 85 patients in the placebo arm (37.6%) and 51 of 177 patients in the RBX2660 arm (28.8%) had experienced recurrence. Though those figures reinforce the superiority of RBX2660 versus placebo, Feuerstadt said the data could also help direct future research into how to further lower the recurrence rate.

“So that really speaks to maybe future studies where we might refortify that in patients that might be at greater risk for recurrence,” he said, “although single dosing—single rectal installation—seems to be the optimal dose.”

RBX2660 has been studied for nearly a decade, including more than 6 controlled clinical trials and more than 1000 participants, according to Ferring. The drug has been granted Fast Track, Orphan, and Breakthrough Therapy designations by the Food and Drug Administration.

Patients who took RBX2660 following antibiotic therapy had lower rates of recurrence and double the time to recurrence, compared to patients taking placebo.

RBX2660 Prolongs Time to Recurrence in Patients with CDI Infection


New clinical trial data suggests an investigational microbiota-based live biotherapeutic leads to a significant reduction in the risk of 

 infection (CDI) recurrence when administered to patients following standard-of-care antibiotics.

American Gastroenterology Association’s Digestive Disease Week

 conference in San Diego, affirm the benefits of using microbiota-based therapeutics to alter patients’ gut microbiota to reduce susceptibility to repeated infection.

Lead author Paul Feuerstadt, MD, of the PACT Gastroenterology Center, told 

 that the biotherapeutic is based on the concept of fecal microbiota transplantation (FMT), a long-established concept in which a stool sample from a healthy donor is transplanted into a patient in hopes of repopulating the recipient’s microbiome with a healthy mix of microorganisms.

While the data behind FMT are encouraging, Feuerstadt said the procedure is still surrounded by significant questions.

“The problem is that there's heterogeneity of those trials, there's heterogeneity of the efficacy analysis, heterogeneity of the safety analysis, but most importantly, there's heterogeneity of the products themselves,” he said.

The heterogeneity within the products means clinicians cannot fully predict the results of a particular FMT procedure, since one healthy sample might vary from the next in important, but hard to define, ways.

That uncertainty has created an opportunity for pharmaceutical products. In this case, Feuerstadt and colleagues investigated Ferring Pharmaceuticals’ RBX2660, a broad-spectrum biotherapeutic product manufactured from live, human-derived microbes that uses standardized screening and controls to ensure the product is safe and its results replicable. The therapy has been granted Fast Track, Orphan, and Breakthrough Therapy designations by the Food and Drug Administration.

“What makes RBX2660 different from a fecal transplant is the broad donor screening—the pathogen screening—which goes well beyond any individual practitioner or really healthcare system’s quality metrics,” he said. “There's also quality metrics on the product, and then a proprietary process creating that broad consortium of spore and non-spore forming bacteria, including bacteroides.”

The newly released data concerns RBX2660’s ability to reduce CDI recurrence versus placebo. The data include subgroup analyses using integrated efficacy results from the PUNCH CD2 phase 2b trial and the PUNCH CD3 phase 3 trial. In the studies, adults with documented recurrent CDI were treated with standard-of-care antibiotics and then randomly assigned to receive either RBX2660 (221 patients) or placebo (131 patients).

After 8 weeks, the data showed RBX2660 had a treatment success rate of 68.3%, compared to 55.0% in the placebo group. Furthermore, the results indicated that the treatment had a similarly high success rate across subgroups based on age, sex, race, number previous CDI episodes, and other factors.

“So really, what we're seeing here is an important signal, which states that across the board regardless of subgroup, its product shows consistent safety and efficacy,” Feuerstadt said. “Previously, we knew that it worked in a broad population, but this really nails it down that you don't need to subgroup the patients and target therapy. This can be used broadly for our patients with recurrent 

Feuerstadt said the data are exciting given the striking effect of CDI on the healthcare system. He noted that about 500,000 people test positive for CDI in the United States each year, and roughly one-quarter of those patients will experience recurrence. Those who experience recurrence face a much higher risk of multiple recurrences, he noted.

Feuerstadt said he hopes these data help lead to FDA approval for RBX2660, potentially in the next 12-16 months, but he said insights from the study and others like it could also be used to expand the use of this type of product to other disease states.

“The future is so bright here,” he said, “and we can see the light at the end of the tunnel.”

The microbiota-based live therapeutic had a 68.3% success rate when administered following antibiotic treatment, versus a 55% success rate in a placebo group.

RBX2660 Cuts Risk of Recurrence in Patients with Multiple C Diff Infections

has become a global public health problem, one intriguing solution has gained more and more traction: fecal microbiota transplantation (FMT).

The theory is well-established: Patients with gut dysbiosis are at a higher risk of recurrent 

 infection. Transplanting a fecal sample from a patient with a healthy gut bacterial community can remediate the patient’s dysbiosis and reduce the risk of infection recurrence. The science is gaining momentum, but Glenn Tillotson, PhD, FIDSA, FCCP, said there is one key consideration with FMT that often gets ignored. There’s more than just bacteria in the gut.

“Bacteria are important, but a donative fecal sample is not just bacteria,” Tillotson said.

While significant energy has been spent understanding the bacteriome and its role in dysbiosis, he said the same is less true for the virome—the complex, heterogeneous collection of viruses present in the gut and in the body as a whole.

“We've all gotten interested in the bacteria,” he said. “We should not ignore the viruses,” he said.

Tillotson, a consultant to the pharmaceutical and health sciences industries, has spent a considerable portion of his career studying 

and FMT. While he is a fan of FMT and its potential, he also argues that an approach that only considers the bacteriome is insufficient. Bacteria, but also viruses and even fungi are also interacting in patients’ guts, and he argues a more holistic view of dysbiosis will yield better, more reliable results.

Tillotson is not alone. Last summer, investigators Guanxiang Liang, PhD, and Frederic Bushman, PhD, of the University of Pennsylvania, published a piece in 

 calling for more attention to be paid to the virome.

They said the technology now exists to better understand and explore the human virome, but they said there is a considerable amount of work yet to be done.

“Despite increasing focus, it remains the case that the majority of sequence data in a typical virome study remain unidentified, highlighting the extent of unexplored viral ‘dark matter,’” they wrote. “Nevertheless, it is now clear that viral community states can be associated with adverse outcomes for the human host, whereas other states are characteristic of health.”

Tillotson noted that the COVID-19 pandemic has brought to the forefront safety concerns with FMT associated with the potential to accidentally transfer harmful organisms into a recipient’s microbiome. FMT samples are screened in order to ensure harmful viruses like SARS-CoV-2 are not present in the donated samples, but Tillotson said the resulting transplant still has plenty of other viruses in it.

“There is still going to be within (the sample) a very large component of viruses,” he said. “The process of screening these donor biological samples doesn't exclude viruses but will only detect adverse deleterious viruses.”

Tillotson and others got a window into the complex interplay in FMT with a recent paper 

 in which corresponding author Satoshi Uematsu, MD, PhD, of Osaka City University Graduate School of Medicine, and colleagues performed metagenomic sequencing on the bacteriomes and viromes of 9 patients who had undergone FMT to treat recurrent 

infection. They concluded that their research provides new fundamental information about how FMT affects donor recipients.

“Our data show that FMT changes the intestinal microflora to resemble more closely that of the physiological healthy state by systemically affecting both the bacteriome and virome of the recipients,” Uematsu and colleagues wrote.

However, they also added that a more detailed analysis of post-transplant viromes and bacteriomes will be necessary to determine how best to optimize the procedure.

Tilottson said the study is a positive step forward, and one he hopes portends a broader mindset among FMT and 

“I think now, we know more about the virome, I think it's time to actually start looking at this milieu of microbiomes such as bacteria and viruses, and how they can potentially work together to enhance a clinical outcome,” he said.

Tillotson said one clear lesson of biology is that nothing sits in a silo. That’s especially true for the microbiome.

“It's something to to make people think that the management of 

 should not be purely bacterial,” he said. “It should be more broad based.”

Liang G, Bushman FD. The human virome: assembly, composition and host interactions. 

. 2021;19(8):514-527. doi:10.1038/s41579-021-00536-5

Fujimoto K, Kimura Y, Allegretti JR, et al. Functional Restoration of Bacteriomes and Viromes by Fecal Microbiota Transplantation. 

. 2021;160(6):2089-2102.e12. doi:10.1053/j.gastro.2021.02.013

Most of the discussion around fecal microbiota transplantation has focused on bacterial communities, but new advances have shed more light on the role of the virome.

In C Diff, New Attention Being Paid to the Role of the Virome

 infection (CDI) who have not responded to metronidazole may benefit from therapy with rifaximin, according to a new report.

The study, which was based on a cohort of 200 patients, suggests rifaximin works best in patients whose diarrhea has had a duration of less than 3 weeks. The study was 

Corresponding author Kiran Abbas, MD, of the Jinnah Postgraduate Medical Center, in Pakistan, and colleagues, noted that both the incidence and severity of CDI has been increasing globally, largely due to an increase in drug-resistant strains of 

. Metronidazole is one of the drugs historically used to treat CDI, but the investigators said the drug is facing higher rates of therapy failure, potentially due to 

. Even when the drug does work, as many as 1 in 4 patients treated with oral metronidazole or 

 experience recurrence, and the rate of recurrence is even higher for subsequent rounds of treatment, they noted.

Abbas and colleagues wrote that they wanted to understand what impact the antibiotic rifaximin might have on patients who were no longer benefiting from metronidazole.

“This drug has been used to counter the recurrence rate of CDI and the results have been enlightening,” Abbas and colleagues wrote. “Rifaximin has also played a role in alleviating the risk of hepatic encephalopathy in patients with decompensated liver disease and even for Crohn's disease.”

However, there is a relative dearth of scientific literature related to rifaximin for recurrent CDI, the authors said.

In the new study, Abbas and colleagues recruited 200 patients who had developed diarrhea following a 7-day course of antibiotics, had a positive 

 stool test, and had been unresponsive to metronidazole.

The patients had a mean age of 45.41 years and had roughly numbers of males and females. The investigators divided the group into 2 cohorts. Patients in the first group were given rifaximin at a dose of 200 mg 3 times per day for 10 days. The other group acted as a control group and was not given a new treatment. The primary endpoints were resolution of diarrhea after 2 weeks of therapy and a negative stool test.

The data showed that rifaximin was effective in about two-thirds (65%) of cases. When analyzing the data to identify factors associated with therapeutic success, the investigators found that age or gender did not matter, but the duration of diarrhea did. Patients whose diarrhea had lasted less than 3 weeks had a success rate of 70.5%, while those with less than 3 weeks of diarrhea had a treatment success rate of 55.3%.

However, the authors said the sample size was too small to more thoroughly consider other factors that might be associated with rifaximin’s success.

Even though rifaximin appeared to lead to promising results, Abbas and colleagues also noted that the potential development of resistance to rifaximin is a concern.

“This is attributed to genetic mutations in the beta subunit of ribonucleic acid (RNA) polymerase,” they wrote. “However, extensive research is required to explore the factors associated with rifaximin resistance to develop strategies to mitigate the process.”

They concluded that future, larger studies should be conducted to validate their results in this patient population.

Waqas M, Mohib K, Saleem A, et al. (April 14, 2022) Rifaximin Therapy for Patients With Metronidazole-Unresponsive Clostridium difficile Infection. 

About 65% of patients with metronidazole-resistant recurrent C difficile infection benefitted from taking rifaximin.

Jared Kaltwasser

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