Placebo

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 1 million deaths in the first 6 months of the pandemic and huge economic and social upheaval internationally. An efficacious vaccine is essential to prevent further morbidity and mortality. Although some countries might deploy COVID-19 vaccines on the strength of safety and immunogenicity data alone, the goal of vaccine development is to gain direct evidence of vaccine efficacy in protecting humans against SARS-CoV-2 infection and COVID-19 so that manufacture of efficacious vaccines can be selectively upscaled. A candidate vaccine against SARS-CoV-2 might act against infection, disease, or transmission, and a vaccine capable of reducing any of these elements could contribute to disease control. However, the most important efficacy endpoint, protection against severe disease and death, is difficult to assess in phase 3 clinical trials. In this Review, we explore the challenges in assessing the efficacy of candidate SARS-CoV-2 vaccines, discuss the caveats needed to interpret reported efficacy endpoints, and provide insight into answering the seemingly simple question, "Does this COVID-19 vaccine work?"

What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2.

A vast and diverse array of microbial species displaying great phylogenic, genomic, and metabolic diversity have colonized the gastrointestinal tract. Resident microbes play a beneficial role by regulating the intestinal immune system, stimulating the maturation of host tissues, and playing a variety of roles in nutrition and in host resistance to gastric and enteric bacterial pathogens. The mechanisms by which the resident microbial species combat gastrointestinal pathogens are complex and include competitive metabolic interactions and the production of antimicrobial molecules. The human intestinal microbiota is a source from which Lactobacillus probiotic strains have often been isolated. Only six probiotic Lactobacillus strains isolated from human intestinal microbiota, i.e., L. rhamnosus GG, L. casei Shirota YIT9029, L. casei DN-114 001, L. johnsonii NCC 533, L. acidophilus LB, and L. reuteri DSM 17938, have been well characterized with regard to their potential antimicrobial effects against the major gastric and enteric bacterial pathogens and rotavirus. In this review, we describe the current knowledge concerning the experimental antibacterial activities, including antibiotic-like and cell-regulating activities, and therapeutic effects demonstrated in well-conducted, placebo-controlled, randomized clinical trials of these probiotic Lactobacillus strains. What is known about the antimicrobial activities supported by the molecules secreted by such probiotic Lactobacillus strains suggests that they constitute a promising new source for the development of innovative anti-infectious agents that act luminally and intracellularly in the gastrointestinal tract.

Anti-Infective Activities of Lactobacillus Strains in the Human Intestinal Microbiota: from Probiotics to Gastrointestinal Anti-Infectious Biotherapeutic Agents

Background International postlicensure studies have identified an increased risk of intussusception after vaccination with the second-generation rotavirus vaccines RotaTeq (RV5, a pentavalent vaccine) and Rotarix (RV1, a monovalent vaccine). We studied this association among infants in the United States. Methods The study included data from infants 5.0 to 36.9 weeks of age who were enrolled in three U.S. health plans that participate in the Mini-Sentinel program sponsored by the Food and Drug Administration. Potential cases of intussusception and vaccine exposures from 2004 through mid-2011 were identified through procedural and diagnostic codes. Medical records were reviewed to confirm the occurrence of intussusception and the status with respect to rotavirus vaccination. The primary analysis used a self-controlled risk-interval design that included only vaccinated children. The secondary analysis used a cohort design that included exposed and unexposed person-time. Results The analyses included 507,874 ...

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Intussusception Risk after Rotavirus Vaccination in U.S. Infants

Intussusception following rotavirus vaccine administration: post-marketing surveillance in the National Immunization Program in Australia

BACKGROUND:Rotavirus results in more diarrhoea-related deaths in children under five years than any other single agent in countries with high childhood mortality. It is also a common cause of diarrhoea-related hospital admissions in countries with low childhood mortality. Rotavirus vaccines that have been prequalified by the World Health Organization (WHO) include a monovalent vaccine (RV1; Rotarix, GlaxoSmithKline), a pentavalent vaccine (RV5; RotaTeq, Merck), and, more recently, another monovalent vaccine (Rotavac, Bharat Biotech). OBJECTIVES:To evaluate rotavirus vaccines prequalified by the WHO (RV1, RV5, and Rotavac) for their efficacy and safety in children. SEARCH METHODS:On 4 April 2018 we searched MEDLINE (via PubMed), the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (published in the Cochrane Library), Embase, LILACS, and BIOSIS. We also searched the WHO ICTRP, ClinicalTrials.gov, clinical trial reports from manufacturers' websites, and reference lists of included studies and relevant systematic reviews. SELECTION CRITERIA:We selected randomized controlled trials (RCTs) in children comparing rotavirus vaccines prequalified for use by the WHO versus placebo or no intervention. DATA COLLECTION AND ANALYSIS:Two review authors independently assessed trial eligibility and assessed risks of bias. One review author extracted data and a second author cross-checked them. We combined dichotomous data using the risk ratio (RR) and 95% confidence interval (CI). We stratified the analysis by country mortality rate and used GRADE to evaluate evidence certainty. MAIN RESULTS:Fifty-five trials met the inclusion criteria and enrolled a total of 216,480 participants. Thirty-six trials (119,114 participants) assessed RV1, 15 trials (88,934 participants) RV5, and four trials (8432 participants) Rotavac. RV1 Children vaccinated and followed up the first year of life In low-mortality countries, RV1 prevents 84% of severe rotavirus diarrhoea cases (RR 0.16, 95% CI 0.09 to 0.26; 43,779 participants, 7 trials; high-certainty evidence), and probably prevents 41% of cases of severe all-cause diarrhoea (RR 0.59, 95% CI 0.47 to 0.74; 28,051 participants, 3 trials; moderate-certainty evidence). In high-mortality countries, RV1 prevents 63% of severe rotavirus diarrhoea cases (RR 0.37, 95% CI 0.23 to 0.60; 6114 participants, 3 trials; high-certainty evidence), and 27% of severe all-cause diarrhoea cases (RR 0.73, 95% CI 0.56 to 0.95; 5639 participants, 2 trials; high-certainty evidence). Children vaccinated and followed up for two years In low-mortality countries, RV1 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.14 to 0.23; 36,002 participants, 9 trials; high-certainty evidence), and probably prevents 37% of severe all-cause diarrhoea episodes (rate ratio 0.63, 95% CI 0.56 to 0.71; 39,091 participants, 2 trials; moderate-certainty evidence). In high-mortality countries RV1 probably prevents 35% of severe rotavirus diarrhoea cases (RR 0.65, 95% CI 0.51 to 0.83; 13,768 participants, 2 trials; high-certainty evidence), and 17% of severe all-cause diarrhoea cases (RR 0.83, 95% CI 0.72 to 0.96; 2764 participants, 1 trial; moderate-certainty evidence). No increased risk of serious adverse events (SAE) was detected (RR 0.88 95% CI 0.83 to 0.93; high-certainty evidence). There were 30 cases of intussusception reported in 53,032 children after RV1 vaccination and 28 cases in 44,214 children after placebo or no intervention (RR 0.70, 95% CI 0.46 to 1.05; low-certainty evidence). RV5 Children vaccinated and followed up the first year of life In low-mortality countries, RV5 probably prevents 92% of severe rotavirus diarrhoea cases (RR 0.08, 95% CI 0.03 to 0.22; 4132 participants, 5 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 57% of severe rotavirus diarrhoea (RR 0.43, 95% CI 0.29 to 0.62; 5916 participants, 2 trials; high-certainty evidence), but there is probably little or no difference between vaccine and placebo for severe all-cause diarrhoea (RR 0.80, 95% CI 0.58 to 1.11; 1 trial, 4085 participants; moderate-certainty evidence). Children vaccinated and followed up for two years In low-mortality countries, RV5 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.08 to 0.39; 7318 participants, 4 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 41% of severe rotavirus diarrhoea cases (RR 0.59, 95% CI 0.43 to 0.82; 5885 participants, 2 trials; high-certainty evidence), and 15% of severe all-cause diarrhoea cases (RR 0.85, 95% CI 0.75 to 0.98; 5977 participants, 2 trials; high-certainty evidence). No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.86 to 1.01; moderate to high-certainty evidence). There were 16 cases of intussusception in 43,629 children after RV5 vaccination and 20 cases in 41,866 children after placebo (RR 0.77, 95% CI 0.41 to 1.45; low-certainty evidence). Rotavac Children vaccinated and followed up the first year of life Rotavac has not been assessed in any RCT in countries with low child mortality. In India, a high-mortality country, Rotavac probably prevents 57% of severe rotavirus diarrhoea cases (RR 0.43, 95% CI 0.30 to 0.60; 6799 participants, moderate-certainty evidence); the trial did not report on severe all-cause diarrhoea at one-year follow-up. Children vaccinated and followed up for two years Rotavac probably prevents 54% of severe rotavirus diarrhoea cases in India (RR 0.46, 95% CI 0.35 to 0.60; 6541 participants, 1 trial; moderate-certainty evidence), and 16% of severe all-cause diarrhoea cases (RR 0.84, 95% CI 0.71 to 0.98; 6799 participants, 1 trial; moderate-certainty evidence). No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.85 to 1.02; moderate-certainty evidence). There were eight cases of intussusception in 5764 children after Rotavac vaccination and three cases in 2818 children after placebo (RR 1.33, 95% CI 0.35 to 5.02; very low-certainty evidence). There was insufficient evidence of an effect on mortality from any rotavirus vaccine (198,381 participants, 44 trials; low- to very low-certainty evidence), as the trials were not powered to detect an effect at this endpoint. AUTHORS' CONCLUSIONS:RV1, RV5, and Rotavac prevent episodes of rotavirus diarrhoea. Whilst the relative effect estimate is smaller in high-mortality than in low-mortality countries, there is a greater number of episodes prevented in these settings as the baseline risk is much higher. We found no increased risk of serious adverse events.

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Vaccines for preventing rotavirus diarrhoea: vaccines in use

Background
Rotavirus results in more diarrhoea-related deaths in children less than five years of age than any other single agent in countries with high childhood mortality. It is also a common cause of diarrhoea-related hospital admissions in countries with low childhood mortality. Currently licensed rotavirus vaccines include a monovalent rotavirus vaccine (RV1; Rotarix, GlaxoSmithKline Biologicals) and a pentavalent rotavirus vaccine (RV5; RotaTeq, Merck & Co., Inc.). Lanzhou lamb rotavirus vaccine (LLR; Lanzhou Institute of Biomedical Products) is used in China only.

Objectives
To evaluate rotavirus vaccines approved for use (RV1, RV5, and LLR) for preventing rotavirus diarrhoea.

Search methods
We searched MEDLINE (via PubMed) (1966 to May 2012), the Cochrane Infectious Diseases Group Specialized Register (10 May 2012), CENTRAL (published in The Cochrane Library 2012, Issue 5), EMBASE (1974 to 10 May 2012), LILACS (1982 to 10 May 2012), and BIOSIS (1926 to 10 May 2012). We also searched the ICTRP (10 May 2012), www.ClinicalTrials.gov (28 May 2012) and checked reference lists of identified studies.

Selection criteria
We selected randomized controlled trials (RCTs) in children comparing rotavirus vaccines approved for use with placebo, no intervention, or another vaccine.

Data collection and analysis
Two authors independently assessed trial eligibility, extracted data, and assessed risk of bias. We combined dichotomous data using the risk ratio (RR) and 95% confidence intervals (CI). We stratified the analysis by child mortality, and used GRADE to evaluate evidence quality.

Main results
Forty-one trials met the inclusion criteria and enrolled a total of 186,263 participants. Twenty-nine trials (101,671 participants) assessed RV1, and 12 trials (84,592 participants) evaluated RV5. We did not find any trials assessing LLR.

RV1
Children aged less than one year: In countries with low-mortality rates, RV1 prevents 86% of severe rotavirus diarrhoea cases (RR 0.14, 95% CI 0.07 to 0.26; 40,631 participants, six trials; high-quality evidence), and, based on one large multicentre trial in Latin America and Finland, probably prevents 40% of severe all-cause diarrhoea episodes (rate ratio 0.60, 95% CI 0.50 to 0.72; 17,867 participants, one trial; moderate-quality evidence). In countries with high-mortality rates, RV1 probably prevents 63% of severe rotavirus diarrhoea cases (RR 0.37, 95% CI 0.18 to 0.75; 5414 participants, two trials; moderate-quality evidence), and, based on one trial in Malawi and South Africa, 34% of severe all-cause diarrhoea cases (RR 0.66, 95% CI 0.44 to 0.98; 4939 participants, one trial; moderate-quality evidence).

Children aged up to two years: In countries with low-mortality rates, RV1 prevents 85% of severe rotavirus diarrhoea cases (RR 0.15, 95% CI 0.12 to 0.20; 32,854 participants, eight trials; high-quality evidence), and probably 37% of severe all-cause diarrhoea episodes (rate ratio 0.63, 95% CI 0.56 to 0.71; 39,091 participants, two trials; moderate-quality evidence). In countries with high-mortality rates, based on one trial in Malawi and South Africa, RV1 probably prevents 42% of severe rotavirus diarrhoea cases (RR 0.58, 95% CI 0.42 to 0.79; 2764 participants, one trial; moderate-quality evidence), and 18% of severe all-cause diarrhoea cases (RR 0.82, 95% CI 0.71 to 0.95; 2764 participants, one trial; moderate-quality evidence).

RV5
Children aged less than one year: In countries with low-mortality rates, RV5 probably prevents 87% of severe rotavirus diarrhoea cases (RR 0.13, 95% CI 0.04 to 0.45; 2344 participants, three trials; moderate-quality evidence), and, based on one trial in Finland, may prevent 72% of severe all-cause diarrhoea cases (RR 0.28, 95% CI 0.16 to 0.48; 1029 participants, one trial; low-quality evidence). In countries with high-mortality rates, RV5 prevents 57% of severe rotavirus diarrhoea (RR 0.43, 95% CI 0.29 to 0.62; 5916 participants, two trials; high-quality evidence), but there was insufficient data to assess the effect on severe all-cause diarrhoea.

Children aged up to two years: Four studies provided data for severe rotavirus and all-cause diarrhoea in countries with low-mortality rates. Three trials reported on severe rotavirus diarrhoea cases and found that RV5 probably prevents 82% (RR 0.18, 95% CI 0.07 to 0.50; 3190 participants, three trials; moderate-quality evidence), and another trial in Finland reported on severe all-cause diarrhoea cases and found that RV5 may prevent 96% (RR 0.04, 95% CI 0.00 to 0.70; 1029 participants, one trial; low-quality evidence). In high-mortality countries, RV5 prevents 41% of severe rotavirus diarrhoea cases (RR 0.59, 95% CI 0.43 to 0.82; 5885 participants, two trials; high-quality evidence), and 15% of severe all-cause diarrhoea cases (RR 0.85, 95% CI 0.75 to 0.98; 5977 participants, two trials; high-quality evidence).

There was no evidence of a vaccine effect on mortality (181,009 participants, 34 trials; low-quality evidence), although the trials were not powered to detect an effect on this end point.

Serious adverse events were reported in 4565 out of 99,438 children vaccinated with RV1 and in 1884 out of 78,226 children vaccinated with RV5. Fifty-eight cases of intussusception were reported in 97,246 children after RV1 vaccination, and 34 cases in 81,459 children after RV5 vaccination. No significant difference was found between children receiving RV1 or RV5 and placebo in the number of serious adverse events, and intussusception in particular.

Authors' conclusions
RV1 and RV5 prevent episodes of rotavirus diarrhoea. The vaccine efficacy is lower in high-mortality countries; however, due to the higher burden of disease, the absolute benefit is higher in these settings. No increased risk of serious adverse events including intussusception was detected, but post-introduction surveillance studies are required to detect rare events associated with vaccination.

Vaccines for preventing rotavirus diarrhoea: vaccines in use (Review)

Background

Rotavirus results in higher diarrhoea-related death in children less than five years of age than any other single agent, particularly in low- and middle-income countries. The World Health Organization has recommended the use of rotavirus vaccines in childhood immunization schedules.



Objectives

To evaluate rotavirus vaccines approved for use (Rotarix, RotaTeq, and Lanzhou Lamb Rotavirus (LLR)) for preventing rotavirus diarrhoea.



Search strategy

In February 2010, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (published in The Cochrane Library 2009, Issue 1), MEDLINE, EMBASE, LILACS, and BIOSIS. We also searched the ICTRP (January 2010) and checked reference lists of identified studies.



Selection criteria

Randomized controlled trials comparing rotavirus vaccines approved for use with placebo, no intervention, or another vaccine in children.



Data collection and analysis

Two authors independently assessed trial eligibility, extracted data, and assessed risk of bias. Dichotomous data were combined using the risk ratio (RR) and 95% confidence intervals (CI).



Main results

Thirty-four trials that included 175,944 participants met the inclusion criteria. They evaluated Rotarix (26 trials; 99,841 participants) and RotaTeq (eight trials; 76,103 participants), and had variable risk of bias (where information provided). None of the identified trials used LLR or compared rotavirus vaccines. Compared to placebo, Rotarix and RotaTeq were both effective at reducing rotavirus diarrhoea (severe cases and cases of any severity). They also reduced all-cause diarrhoea (severe cases), and hospitalizations and need for medical attention caused by rotavirus diarrhoea. However, few data were available for Rotarix and all-cause diarrhoea. Versus the placebo groups, participants in each vaccine group had similar numbers of deaths, serious adverse events, reactogenicity profiles (fever, diarrhoea, and vomiting), and adverse events that required discontinuation of the vaccination schedule. Both vaccines were immunogenic (measured by virus shedding in stool and/or seroconversion). Subgroup analyses indicate that both vaccines are effective in countries with different incomes, but few data are available.



Authors' conclusions

Rotarix and RotaTeq are effective vaccines for the prevention of rotavirus diarrhoea. The balance between benefit and harm favours benefit. Ongoing safety monitoring should be continued. Trials comparing LLR with placebo should be conducted and the results made available.



Plain Language Summary

Vaccines for preventing rotavirus diarrhoea: vaccines in use



Rotavirus infection is the most common cause of diarrhoea in infants and young children, and the symptoms can range from non-severe illness, to hospitalization and death. Rotavirus infections cause over half a million deaths per year in children younger than five years, especially in low- and middle-income countries. Since 2009, the World Health Organization has recommended vaccination be included in national immunization programmes.



This review evaluates three vaccines currently in use: Rotarix and RotaTeq, which have been evaluated in several large trials and are approved for use in many countries; and Lanzhou Lamb Rotavirus vaccine (LLR), which is approved for use in China only.  



The review includes 34 trials with about 175,944 participants; all trials compared a rotavirus vaccine with a placebo. The vaccines tested were Rotarix (26 trials with 99,841 participants) and RotaTeq (eight trials with 76,103 participants). None of the identified trials used LLR. The trials took place all over the world.



Compared to placebo, Rotarix and RotaTeq were both effective at reducing rotavirus diarrhoea. They also reduced severe diarrhoea from all causes, hospitalizations and need for medical attention. The vaccines were particularly effective at one and two years of follow-up. The vaccines tested against placebo gave similar numbers of adverse events such as deaths, reactions to the vaccine, and others that required discontinuation of the vaccination schedule.



In conclusion, data from this review show that Rotarix and RotaTeq are effective vaccines, and support the World Health Organization's recommendation to include rotavirus vaccination of infants into national immunization programmes, especially in countries with a high burden of diarrhoeal deaths in children younger than five years. New trials with head-to-head comparisons of both vaccines are needed, as well as trials comparing LLR with placebo, data for special groups of children, such as preterm infants and malnourished children, and extensive monitoring of adverse events where vaccines are routinely used.

Irit Ben-Aharon

Papers

Vaccines for preventing rotavirus diarrhoea: vaccines in use

Vaccines for preventing rotavirus diarrhoea: vaccines in use (Review)

Cochrane review: Vaccines for preventing rotavirus diarrhoea: vaccines in use