Virus World

New Coronavirus Disease 2019 (COVID-19) vaccines are available to prevent the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. We compared the efficacy of new COVID-19 vaccines to prevent symptomatic and severe disease in the adult population and to prevent symptomatic COVID-19 among the elderly. Leading medical databases were searched until August 30, 2021. Published phase 3 randomized controlled trials (RCTs) evaluated efficacy of the vaccine to prevent symptomatic and sever COVID-19 in adults were included. Two reviewers independently evaluated the literature search results and independently extracted summary data. The risk of bias was evaluated using the Cochrane Risk of Bias Assessment Tool. We performed a network meta-analysis (NMA) according to PRISMA-NMA 2015 to pool indirect comparisons between different vaccines regarding their relative efficacy. The primary outcomes were the efficacy of the vaccine against symptomatic COVID-19 in adults (PROSPERO registration number: CRD42021235364). Above 200,000 adult participants from eight phase 3 RCTs were included in NMA, of whom 52% received the intervention (active COVID-19 vaccine).

While each of nine vaccines was tested in the unique clinical trial as compared to control, based on indirect comparison, BNT162b2 and mRNA-1273 vaccines were ranked with the highest probability of efficacy against symptomatic COVID-19 (P-scores 0.952 and 0.843, respectively), followed by Gam-COVID-Vac (P-score 0.782), NVX-CoV23730 (P-score 0.700), CoronaVac (P-score 0.570), BN02 (P-score 0.428), WIV04 (P-score 0.327), and Ad26.COV2.S (P-score 0.198). No statistically significant difference was seen in the ability of the vaccines to prevent symptomatic disease in the elderly population. No vaccine was statistically significantly associated with a decreased risk for severe COVID-19 than other vaccines, although mRNA-1273 and Gam-COVID-Vac have the highest P-scores (0.899 and 0.816, respectively), indicating greater protection against severe disease than other vaccines. In our indirect comparison, the BNT162b2 and mRNA-1273 vaccines, which use mRNA technology, were associated with the highest efficacy to prevent symptomatic COVID-19 compared to other vaccines. This finding may have importance when deciding which vaccine to use, together with other important factors as availability of the vaccines, costs, logistics, side effects, and patient acceptability.

Published November 23, 2021 in Scientific Reports:

https://doi.org/10.1038/s41598-021-02321-z 

Study finds antibodies against Sars-CoV-2 three-and-a-half times higher in people vaccinated again after 12 weeks rather than three. The UK’s decision to delay second doses of coronavirus vaccines has received fresh support from research on the over-80s which found that giving the Pfizer/BioNTech booster after 12 weeks rather than three produced a much stronger antibody response. A study led by the University of Birmingham in collaboration with Public Health England found that antibodies against the virus were three-and-a-half times higher in those who had the second shot after 12 weeks compared with those who had it after a three-week interval. Most people who have both shots of the vaccine will be well protected regardless of the timing, but the stronger response from the extra delay might prolong protection because antibody levels naturally wane over time.  Dr Helen Parry, a senior author on the study at Birmingham, said: “We’ve shown that peak antibody responses after the second Pfizer vaccination are really strongly boosted in older people when this is delayed to 11 to 12 weeks. There is a marked difference between these two schedules in terms of antibody responses we see.” In the first weeks of the vaccine programme the UK took the bold decision to delay administering booster shots so that more elderly and vulnerable people could more quickly receive their first shots.

The move was controversial because medicines regulators approved both the Pfizer/BioNTech and Oxford/AstraZeneca vaccines on the basis of clinical trials that spaced out the doses by only three or four weeks. Researchers from Oxford University showed in February that antibody responses were more than twice as strong when boosters of their vaccine were delayed for 12 weeks. But the latest study is the first to compare immune responses after different timings with the Pfizer/BioNTech jab. The scientists analysed blood samples from 175 over-80s after their first vaccine and again two to three weeks after the booster. Among the participants 99 had the second shot after three weeks, while 73 waited 12 weeks. After the second dose, all had antibodies against the virus’s spike protein, but the level was 3.5 times higher in the 12-week group. The researchers then looked at another arm of the immune system, the T cells that destroy infected cells. They found that T cell responses were weaker when the booster was delayed, but settled down to similar levels when people were tested more than three months after the first shot. Details are published in pre-print form and have yet to be peer reviewed. “This study further supports the growing body of evidence that the approach taken in the UK of delaying that second dose has really paid off,” said Dr Gayatri Amirthalingam, consultant epidemiologist at Public Health England. 

“Individuals need to really complete their second dose when it’s offered to them because it not only provides additional protection but potentially longer lasting protection against Covid-19.” The findings come as new data from Public Health England suggested that the vaccination programme had prevented 11,700 deaths by the end of April 2021 in those aged 60 and over, and at least 33,000 hospitalisations in those aged 65 and over in the same period.  “Overall, these data add considerable support to the policy of delaying the second dose of Covid-19 vaccine when vaccine availability is limited and the at-risk population is large,” said Eleanor Riley, professor of immunology and infectious disease at the University of Edinburgh. “Longer term follow-up of this cohort will help us to understand which vaccine interval will be optimal in the future, once the immediate crisis is over.”

Preprint available in medRxiv (May 17, 2021):

https://doi.org/10.1101/2021.05.15.21257017 

Background

Methods

Findings

Interpretation

The AstraZeneca vaccine, developed in partnership with Oxford University, is the third to announce positive trial results this month. AstraZeneca said Monday that its coronavirus vaccine reduced the risk of symptomatic Covid-19 by an average of 70.4%, according to an interim analysis of large Phase 3 trials conducted in the United Kingdom and Brazil. The results, while positive, suggest the vaccine may be less effective than two others. Earlier this month, Moderna and the Pfizer and BioNTech consortium announced their messenger RNA, or mRNA, vaccines showed 95% efficacy against Covid-19 infections in their respective clinical trials. Still, researchers at the University of Oxford, which partnered with AstraZeneca to develop the vaccine, hailed the latest data as promising. “The announcement today takes us another step closer to the time when we can use vaccines to bring an end to the devastation caused by SARS-CoV-2,” Sarah Gilbert, one of the co-developers of the vaccine, said in a statement.

The preliminary results on the AstraZeneca vaccine were based on a total of 131 Covid-19 cases in a study involving 11,363 participants. The findings were perplexing. Two full doses of the vaccine appeared to be only 62% effective at preventing disease, while a half dose, followed by a full dose, was about 90% effective. That latter analysis was conducted on a small subset of the study participants, only 2,741. A U.S.-based trial, being supported by Operation Warp Speed, is testing the two-full-dose regimen. That may soon change. AstraZeneca plans to explore adding the half dose-full dose regimen to its ongoing clinical trials in discussions with regulatory agencies, a spokesman told STAT in an email. “We see a lot of merit in this regimen and we will now start discussions with regulators into incorporating this dose combination for further clinical investigation,’’ Brendan McEvoy said. Why would less vaccine produce a better result?  “That’s a good question,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told STAT. Fauci suggested “there’s going to be a lot of hand waving” as people try to explain the results. If a final analysis, conducted after the inclusion of additional data, concludes the vaccine’s actual efficacy is around 70%, that could be a problem. “If it’s 70%, then we’ve got a dilemma,” said Fauci. “Because what are you going to do with the 70% when you’ve got two [vaccines] that are 95%? Who are you going to give a vaccine like that to?” He noted, though, that full datasets — which the Oxford researchers said they intend to publish in a scientific journal — need to be pored over before conclusions can be drawn. “We’ve got to look at the analyses, the real granular data. It’s always tough when you’re looking at a press release to figure out what’s going on,” Fauci said.

The Oxford researchers suggested the vaccine may reduce transmission of the virus, because they saw fewer asymptomatic cases in their trial. One of the challenges of controlling spread of the SARS-CoV-2 virus is that some people who become infected have no symptoms but can still transmit the virus. There were no hospitalized or severe cases of Covid-19 reported in the studies. No serious safety events related to the vaccine occurred in the studies, AstraZeneca said. Results from the U.S. trial will be delayed because that trial was paused for more than a month after one of the participants in the U.K. trial developed a rare but neurological condition, described as consistent with transverse myelitis. The Food and Drug Administration allowed the trial to resume in late October. AstraZeneca said in a release that it intends to seek emergency use authorizations in countries around the world that have a regulatory framework that allows for conditional or early approval of medical products, and will seek an emergency use listing from the World Health Organization, a pathway to rapid approval for low-income countries. The vaccine can be stored at normal refrigeration temperatures for up to six months, which will make it easier to deploy in more settings than the vaccines from Pfizer and Moderna, which must be stored at ultra-low temperatures. The Pfizer vaccine must be stored at -94 degrees Fahrenheit, while the Moderna must be stored at -4 F. Once thawed, Moderna’s vaccine can be stored at fridge temperature for a month. “The vaccine’s simple supply chain and our no-profit pledge and commitment to broad, equitable and timely access means it will be affordable and globally available,” AstraZeneca CEO Pascal Soriot said in a statement. AstraZeneca said it is on track to be able to produce 3 billion doses of its vaccine in 2021.

AstraZeneca's release (Nov. 23, 2020):

https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html

It doesn't take an epidemiologist to evaluate vaccine trial results. Answers to just a handful of questions can help anyone do this. Monday marked the first announcement of preliminary results of Phase 3 trials of Covid-19 vaccines, and we expect many more to follow. These results are long awaited: Mass vaccination will give us the most promising path out of the pandemic — but only if people trust the results enough to get the vaccine. A well-informed public is among the most crucial elements of a successful vaccination program. It doesn’t take an epidemiologist to thoughtfully evaluate vaccine trial results. Answers to just a handful of questions can help anyone compare their strengths and weaknesses, distinguish the promising from the inadequate, and know when more information is needed to figure out which is which. Did the vaccine reduce symptomatic infections? No vaccine is 100% protective. The best of the bunch, like vaccines against the measles and hepatitis A, reduce infections in about 95% of people. Yet many other vaccines, such as those for influenza and typhoid, are closer to a coin flip — getting vaccinated reduces the risk of infection by about half. What is the target for Covid-19 vaccines? The FDA has set an efficacy threshold of a 50% reduction in symptomatic infections for consideration of licensure (total and severe infections are harder to measure — more on that later). But experts would like to see something closer to a 60% to 70% reduction, which would bring us closer to approaching herd immunity and potentially allow us to start relaxing physical distancing measures. This is one reason why the 90% reduction reported this week by Pfizer and BioNTech in the first trial results are particularly exciting.

Who participated in the study? Three groups are key: people older than 65; underrepresented racial and ethnic groups, particularly Black and Latino populations; and individuals with medical conditions such as kidney disease, diabetes, or obesity. Study after study after study has shown that these groups suffer the greatest burden of Covid-19-related complications and death. So a vaccine that reduces disease severity in young, healthy white people but has a little effect in these higher-risk groups might have considerably less public health impact. Pharmaceutical companies have been called upon for years to increase diversity in clinical trials, particularly among historically marginalized and exploited groups. Although the Phase 3 trials for Covid-19 vaccines are not large enough to separately show benefit or harm in each of these groups, inclusion of equitable numbers will be crucial for broad public trust in trial results. What do the results reveal about severe infections? On first glance, this might seem like a rehash of the first point, about whether the vaccine reduced symptomatic infections. But the distinction is very important. A vaccine that only moderately prevents infections but that strongly reduces hospitalizations or deaths could still be a winning candidate. It would convert Covid-19 into something akin to the common cold — an annoyance, but not a life-threatening infection. Reducing disease severity may also make people less likely to transmit the virus to others, another win. Because severe Covid-19 infections are relatively uncommon — occurring more often in the elderly, less so in young, healthy people — showing a large benefit in reducing disease severity won’t be easy. For example, the clinical trial plans for the Pfizer/BioNTech vaccine calls for enrolling approximately 43,000 people to detect just 160 symptomatic infections when the final results are released (there were 96 detected symptomatic infections at the time of the preliminary analysis). No data on severe infections have been reported so far, but we would expect only about two dozen of the 160 infected to be hospitalized and a few to die, leaving little chance to show that the vaccine prevents severe complications. Nonetheless, even a modest effect on Covid-19 severity would be welcome, especially if it occurs among the vulnerable groups discussed earlier.

Is it safe? Since vaccines are mainly given to healthy people — and in this case, potentially to billions of them — understanding the safety of a Covid-19 vaccine is essential. Some good news is that the vaccine candidates under consideration are unlikely to have common severe side effects such as a severe allergic reaction or rash requiring hospitalization. They have completed Phase 2 trials that demonstrated safety in hundreds of people. Any vaccine that caused severe side effects in more than 10% of the Phase 2 participants would not have moved ahead into these larger trials....

Scores of Covid vaccines are in development. Four companies have manufactured the majority of doses. But that doesn't mean they are the best. P fizer/BioNTech. Moderna. Johnson & Johnson. AstraZeneca. These are the marquee names that spring to mind when you think of the vaccine companies at the forefront of the global fight against Covid-19. And for good reason: together they have manufactured the majority of the estimated 7 billion-plus Covid vaccine doses administered to date around the world.  But as regulators in the U.S., Europe, and around the world mull the most responsible way to expand vaccine eligibility to an even larger share of their populations — including to younger children, as the Food and Drug Administration (FDA) and Centers for Disease Control (CDC) have done this month by greenlighting Pfizer’s vaccine for kids 5 to 11 years of age — it’s time to confront an uncomfortable reality: The global health community still doesn’t know which of the hundreds of Covid vaccines currently in clinical and preclinical development are truly “the best.” That’s a shortcoming governments and the global health system need to address if they are to ensure that the next pandemic doesn’t knock the world on its heels to the extent the novel coronavirus has done.  Of the 128 Covid vaccines currently being clinically tested (21 of which have been cleared for use in general populations), Pfizer, Moderna, J&J, and AstraZeneca manufacture just four, according to the latest World Health Organization (WHO) data. Russia’s Sputnik V jab is being distributed in 39 countries with dozens of other markets potentially on the horizon; Sinovac and Sinopharm, both of China, have delivered nearly half of the world’s vaccine doses to date; Bharat Biotech in India won WHO emergency use approval for its Covid shot earlier this month. These are just a handful of the other companies with vaccines that are being given to people in many low- and middle-income countries. Another 194 candidates are in preclinical development in labs or being tested in animals.

These companies and their products are largely unknown outside of the life sciences industry, some academic institutions, and government-backed public health centers. But just because massive, globally established pharmaceutical companies and universities have fueled the world’s vaccine supply to date doesn’t mean they have created the best ones. Other vaccines may prove to be more effective, or safer, or more appropriate for a certain coronavirus variant or among certain age groups in the coming years as the march of SARS-CoV-2, the virus that causes Covid-19, is slowed and it becomes endemic. To be clear, I am not denigrating the safety and effectiveness of the most common and widely used Covid-19 vaccines. But as with so many other facets of public health, the pandemic has turned a glaring light on a long-festering problem: There is no unifying framework for what makes a vaccine “best.” This shortcoming inevitably leads to R&D and manufacturing imbalances down the line as dominant pharmaceutical players leverage their access to institutions and capital to leapfrog the vaccines-that-might-have-been.  The first essential step in addressing this failure is establishing a working definition of what constitutes “best” in vaccine development. Key data points to consider will include safety and effectiveness across coronavirus variants; short-, medium-, and long-term immunity; safety; and overall real-world health outcomes.

Should the level of neutralizing antibodies produced by a vaccine and their staying power be the metric by which it is judged? Should one vaccine be prioritized in certain geographic locations over another because different demographics respond to various jabs in different ways? Those questions need answers. Randomized clinical trials, the gold standard for sniffing out effective medicines, conducted early in the development process must be paired with monitoring real-world evidence for an evolving virus, like the data being collected in the 427 ongoing observational Covid-19 studies the WHO has tracked so far. Head-to-head clinical trials that compare one vaccine directly against another have their uses as well, but don’t address the underlying dilemma of defining exactly which qualities you’re looking for in a vaccine. And with hundreds of vaccine candidates, it’s simply implausible to conduct head-to-head studies of all of them. The focus, then, must be on ensuring that the vaccines most likely to be best are supported early. That requires a level of consensus on critical issues such as proper endpoints and goals, whether a vaccine is keeping people out of the hospital or preventing breakthrough infections, as well as more consistency in clinical trial enrollment, such as whether or not a study assesses a jab in children ages 5 to 12 rather than ages 5 to 11.  Beyond those clinical fundamentals, vaccines for Covid-19 or future infectious disease threats cannot reach their full potential without adequate investment and funding mechanisms guided by science.

The vaccines that have been granted approvals or authorizations to date have been the best funded, either through government programs such as Operation Warp Speed or private funding, while other candidates have stalled for lack of access to capital that can facilitate a quick manufacturing ramp-up to meet the moment’s need. If the same kind of global emergency were to emerge again, the system for advancing vaccine candidates currently in place would be no better — and perhaps would be even worse — without gargantuan ad hoc measures like Operation Warp Speed at play. By default, the current pandemic response has revealed a system where finance is a proxy for “best,” as if it was a betting market, rather than letting science guide resource allocation. There is currently no set of mutually recognized guidelines by which to rationalize investment in global vaccines, even though the U.S. will accept WHO “recognition” of a vaccine as sufficient for immunized travelers wishing to come into the country. But there is no prospect of the European Union, the United Kingdom, the U.S., and countries around the world working together “next time.” This is not a sustainable dynamic if we are to prevent, or at the very least mitigate, the public health catastrophes of tomorrow. Global health experts at the WHO and beyond had been warning that the world is fundamentally unprepared for such a calamitous event years before Covid-19 reared its head. And there has been a common theme in critiques of the existing vaccine infrastructure: There must be a mutual recognition around the world of rationalizing investment in vaccines of the future to outsmart yet-unknown pathogenic foes. Some of the world’s leading health organizations, such as the Coalition for Epidemic Preparedness Innovations (CEPI) and think tanks such as the Peterson Institute for International Economics, have already proposed common-sense improvements to the vaccine discovery, development, and evaluation process that can also make a tangible difference in manufacturing and distributing vaccines down the line. These are “portfolio” approaches meant to take a vaccine through its full life cycle, from discovery to real-world deployment. For instance, Peterson’s Reinhilde Veugelers, a professor in the department of management, strategy, and innovation at KU Leuven in Belgium, penned a report in March on the level of public and private investment necessary for both discovering and identifying the best vaccines in future pandemics and making sure they are effectively distributed across the globe.

“Because of the high risks associated with research projects, and the high social cost of failure, we need multiple vaccine candidates and technologies simultaneously. Public resources should especially support (or at least not bias against) the early stage, riskiest projects, which offer the greatest promises for big breakthroughs. Risks can be managed by diversifying and staging grants,” she writes. Veugelers goes on to note that this portfolio approach, which will almost inevitably mean government support for programs that will eventually fail, necessitates proactive investment at both the cheaper, early developmental stages and the far costlier long-term prospect of mass vaccine production and distribution. GAVI, the International Vaccine Institute, and CEPI laid out concrete steps on how to make sure promising vaccines are effectively distributed in an unpredictable pandemic environment in an article in the journal Nature Medicine:

• Standardize labeling of vaccines so they can be interchanged across countries and regions;
• Use date of production rather than expiration so shelf life can be tracked;
• Adopt three-dimensional bar coding to allow critical information to be updated;
• Employ standard indemnification and liability language that provides protection for manufacturers;
• Create no-fault compensation mechanism for serious adverse events related to vaccine administration;
• Harmonize regulations.

Pharmaceutical innovation requires constant reinvention and the ability to adapt to shifting circumstances while carrying forth the lessons learned from previous shortcomings. The world faces a tough set of choices on how to change existing structures of pandemic preparedness and vaccine development if it is to ward off the next worldwide threat. And that conversation must begin with the acknowledgment that the status quo cannot ensure a different, better outcome in the coming years and decades.

Mike Rea is a biopharmaceutical industry and innovation expert, a senior fellow at the Milken Institute’s FasterCures center, and the CEO of IDEA Pharma and Protodigm

Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4–28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7–13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic. Estimates of the levels of neutralizing antibodies necessary for protection against symptomatic SARS-CoV-2 or severe COVID-19 are a fraction of the mean level in convalescent serum and will be useful in guiding vaccine rollouts.

Published in Nature Medicine (May 17, 2021):

https://www.nature.com/articles/s41591-021-01377-8 

(Reuters) - AstraZeneca and Oxford University’s COVID-19 vaccine is more effective when its second dose is given three months after the first, instead of six weeks, a peer-reviewed study published in The Lancet medical journal showed on Friday. The study confirmed the Anglo-Swedish drugmaker’s findings from earlier this month that showed the vaccine had 76% efficacy against symptomatic coronavirus infection for three months after the first dose. Efficacy was found to be at 81% with the longer interval of 12 weeks between the first and second dose, compared with 55% efficacy up to the six-week gap, according to the Lancet study, which backs British and WHO recommendations for longer intervals. (bit.ly/3bmLX25) Faced with a resurgence in infections and new, highly transmissible variants of the virus, many countries are hoping to broaden immunization by giving some protection to as many people as possible with a first dose, while delaying subsequent shots.

Findings in The Lancet (Feb. 19, 2021):

http://www.thelancet-press.com/embargo/oxfordvaccineinterval.pdf 

You might assume that 95 out of every 100 people vaccinated will be protected from Covid-19. But that’s not how the math works. The front-runners in the vaccine race seem to be working far better than anyone expected: Pfizer and BioNTech announced this week that their vaccine had an efficacy rate of 95 percent. Moderna put the figure for its vaccine at 94.5 percent. In Russia, the makers of the Sputnik vaccine claimed their efficacy rate was over 90 percent. “These are game changers,” said Dr. Gregory Poland, a vaccine researcher at the Mayo Clinic. “We were all expecting 50 to 70 percent.” Indeed, the Food and Drug Administration had said it would consider granting emergency approval for vaccines that showed just 50 percent efficacy. From the headlines, you might well assume that these vaccines — which some people may receive in a matter of weeks — will protect 95 out of 100 people who get them. But that’s not actually what the trials have shown. Exactly how the vaccines perform out in the real world will depend on a lot of factors we just don’t have answers to yet — such as whether vaccinated people can get asymptomatic infections and how many people will get vaccinated.  Here’s what you need to know about the actual effectiveness of these vaccines.

What do the companies mean when they say their vaccines are 95 percent effective?

The fundamental logic behind today’s vaccine trials was worked out by statisticians over a century ago. Researchers vaccinate some people and give a placebo to others. They then wait for participants to get sick and look at how many of the illnesses came from each group. In the case of Pfizer, for example, the company recruited 43,661 volunteers and waited for 170 people to come down with symptoms of Covid-19 and then get a positive test. Out of these 170, 162 had received a placebo shot, and just eight had received the real vaccine. From these numbers, Pfizer’s researchers calculated the fraction of volunteers in each group who got sick. Both fractions were small, but the fraction of unvaccinated volunteers who got sick was much bigger than the fraction of vaccinated ones. The scientists then determined the relative difference between those two fractions. Scientists express that difference with a value they call efficacy. If there’s no difference between the vaccine and placebo groups, the efficacy is zero. If none of the sick people had been vaccinated, the efficacy is 100 percent. A 95 percent efficacy is certainly compelling evidence that a vaccine works well. But that number doesn’t tell you what your chances are of becoming sick if you get vaccinated. And on its own, it also doesn’t say how well the vaccine will bring down Covid-19 across the United States.

What’s the difference between efficacy and effectiveness?

Efficacy and effectiveness are related to each other, but they’re not the same thing. And vaccine experts say it’s crucial not to mix them up. Efficacy is just a measurement made during a clinical trial. “Effectiveness is how well the vaccine works out in the real world,” said Naor Bar-Zeev, an epidemiologist at the Johns Hopkins Bloomberg School of Public Health. It’s possible that the effectiveness of coronavirus vaccines will match their impressive efficacy in clinical trials. But if previous vaccines are any guide, effectiveness may prove somewhat lower. The mismatch comes about because the people who join clinical trials are not a perfect reflection of the population at large. Out in the real world, people may have a host of chronic health problems that could interfere with a vaccine’s protection, for example. The Centers for Disease Control and Prevention has a long history of following the effectiveness of vaccines after they’re approved. On Thursday, the agency posted information on its website about its plans to study the effectiveness of coronavirus vaccines. It will find opportunities to compare the health of vaccinated people to others in their communities who have not received a vaccine....

A recent publication by a Stanford scientist, Bali Pukendran, reviews how the microbiome may play a key role in vaccines efficacy.

Multiples examples have highlighted the role of the microbiota. Earlier studies have evaluated the role of the microbiota small animal models in which  depletion of their microbiota by antibiotics or the testing with germ-free animals resulted in reduced vaccine efficacies. Other studies in human have helped understand how the microbiome influences vaccine's responses by monitoring the vaccine's  signature. The use of  artificial intelligence has been used to predict immune responses.

Immunization with influenza vaccines led to the discovery of potential  links with the microbiota.  The inactivated influenza vaccine induces expression of Toll-like-receptor 5 (TLR5), a key protein recognizing  bacterial components and triggering an innate immune response. Mice deficient in tlr5 induce poor anti-influenza antibody  responses upon vaccination. Similar results have been observed with an adjuvant-free polio vaccine, but not with vaccines containing adjuvants, suggesting that the microbiota may act as an endogenous adjuvant, and may play an even more important role when the individuals have no pre-existing immunity against the pathogen the are immunized against.

Several studies have revealed that in addition to specific gene signatures, antibiotics also lead to significant changes in the blood metabolome, including changes in bile acids that have been shown to modulate inflammatory responses in humans. Furthermore, age may increase gut permeability, exacerbating the effects of the bacterial metabolome and perhaps playing a role in the limited  vaccine efficacy observed in elderly patients.

These findings highlights the importance of avoiding antibiotic use during vaccination, especially in children, where pre-existing responses may be limited. They also highlight the importance to stratify patients in vaccine trials by their microbiomes and bacterial metabolomes, to better elucidate which patients better response to future experimental vaccines.

Published in Science (29 November , 2019):

https://doi.org/10.1126/science.aau6975