A massive funding boost from Project NextGen enables 3 phase 2b trials of next generation Covid vaccines to start in the US…
There could be well over 20 million children under 5 Covid-vaxed globally – the vast majority in China, and nearly all with Chinese inactivated vaccines. Hundreds of thousands have been vaccinated with protein subunit and conjugate vaxes from Cuba. That’s 5 vaccines in all, authorized in 8 countries, starting from 2 or 3 years of age. Being able to extend vaccination to almost every age has helped several countries to get well over 90% of their populations Covid-vaxed.
On top of that, there is some off-label use. That’s when doctors use approved vaccines for people who aren’t covered by that approval. Off-label use of Covid vaccines has been discouraged in the US. In Canada, a doctor who said he had vaccinated more than 500 children off-label was warned about this, and stopped. There is a report on how often the vaccine has been used off-label in that province, but it doesn’t seem to be public.
The only data I’ve seen on off-label use of Covid vax in the under-5s comes from Germany. Researchers contacted 19,000 of the families with children under 5 who received the Pfizer vaccine off-label, and thousands participated. This post covers that study, as well as studies in countries where vaccines have been rolled out, along with clinical trial results. There are at least some results in the under-5s for 4 of the 5 authorized vaccines, plus those from Moderna, Pfizer, and India’s Covaxin. And there are trials underway in this age group for another 5 vaccines.
These are the key points I take away from the data in this post:
- In the doses tested, vaccine adverse reactions are fairly similar to those in older children and young people – with one apparent exception.
- That exception is the Pfizer vaccine. If the data bears out the claim in the company’s press release, the very low dose used means the 3-dose course for under-5s has a rate of adverse events similar to a placebo injection. That would be much lower per injection than for other ages.
- In the doses used, for most of the 8 vaccines that are either authorized or have results released, efficacy appears broadly similar for the very young to other age groups – and that includes being less effective against recent variants of concern. (There’s a vaccine with no public data at all, though, a couple with very little, and I’ve put a question-mark on another.)
- Vaccination of the very young was too recent in these studies to indicate whether effect wanes as it can in other age groups.
Before we begin digging into data for the under-5s, I think there are a couple of points to keep in mind for context. The first is to expect studies that might seem small. Once a vaccine has already been shown to prevent disease outcomes, studies tend to be designed to confirm whether signs of immune response are similar when the vaccine is used by another group: fewer trial participants are needed to do that and evaluate common short-term reactions. Secondly, results after rollout and in trials done later in the pandemic are facing variants that can reduce vaccine effectiveness for children as it does for adults.
Here’s some data from 5+ age groups with the Pfizer vaccine that shows how all that can play out:
- Number of 16-17 year-olds in the trial when the vax was approved for that age group: 153 (for both ages). (That was controversially low.)
- Number of 5-11 year-olds in the trial when it was approved for them: 2,268 (for the 7 ages).
- Vaccine effectiveness in the trial for 5-11 year-olds was 90.7% (CI 68-98)* against symptomatic disease. Whereas without boosters for during the Omicron wave it was:
- Against infection (including asymptomatic): 24% (CI 21-28) in one study, 31% (CI 9-48) in another;
- Against emergency/urgent care visit: 51% (CI 30-65);
- Against hospitalization: 68% (CI 42-82).
* Explanation: Vaccine efficacy or effectiveness is a rate of risk reduction – how much a person’s risk is reduced if they’re exposed to the virus. It’s not an absolute reduction in percentage points. The CI numbers in parentheses show a range of statistical uncertainty (a confidence interval). When it’s smaller – like that 21-28 above – it means there’s more certainty in that dataset than when the range is very large (like all the others above).
And finally, here’s a list of contents to help you navigate to the info you’re interested in:
- Which Covid vaccines have been rolled out for under-5s and where
- Summary of results for authorized and other vaccines in under-5s:
- Other vaccines in trials for under-5s
- Addendum: Table of vaccines with study results for under-5s (including details and links for all the trials in progress for those vaccines in this age group)
Notes on sources: For details on how I track Covid vaccine progress, see my background post. Notes on my collection of studies are here. The collection is in a public Zotero library you can dig into here.
Vaccine rollouts to under-5s
Three Covid vaccines have been authorized for use in under-5s in 8 countries as far as I know (counting Hong Kong), mostly 2-dose inactivated vaccines from China – Sinopharm (Beijing vax) and Sinovac (CoronaVac). The Soberana combination of protein subunit vaccines in 3 doses from Cuba is the third vaccine rolled out for the under-5s. Another 2 countries may be close to rolling out vaccines: the US FDA has convened a meeting on June 15 to discuss applications from Moderna and Pfizer for use from 6 months of age, and Brazil’s regulator, Anvisa, is evaluating Sinovac’s CoronaVac for 3-5 year-olds. For rough context, the proportion of the US population under the age of 5 is about 6%, and for Brazil, it’s 7%.
Current rollouts (in alphabetical order):
- Argentina: The 2-dose Sinopharm Beijing vaccine was authorized for 3-11 year-olds in October 2021. Around the start of 2022, 70% in that age group had received at least a dose, but the proportion under 5 isn’t included in the country’s monitoring report.
- For context, the proportion of the population of Argentina under 5 is over 8%.
- Bahrain: The 2-dose Sinopharm vaccine was authorized for 3-11 year-olds there too in October 2021.
- The proportion of the population of Bahrain under 5 is over 6%.
- Chile: CoronaVac, the Sinovac vaccine, was authorized from 3 years of age in December 2021.
- China: Both the Sinopharm and Sinovac vaccines were authorized for 3-11 year-olds in June 2021. By November 2021, over 84 million in that age group had at least 1 dose.
- The proportion of the population under 5 is close to 6%.
- Cuba: The 3-dose Abdala vaccine was authorized from age 2 at the end of October 2021. Soberana vaccine – 2 doses of Soberana-2 plus a dose of Soberana-Plus – were authorized from age 2 in December 2021. Children who have had Covid get a single dose of Soberana-Plus.
- The proportion of the population under 5 is 5%. The proportion of the whole population with at least 1 dose is 94%.
- Hong Kong: CoronaVac, the Sinovac vaccine, was authorized from age 3 in February 2022.
- The proportion of the population under 5 is 5%.
- United Arab Emirates: The Sinopharm vaccine was authorized for 3-11 year-olds there in August 2021.
- The proportion of the population under 5 is 5%. The proportion of the whole population with at least 1 dose is 99%.
- Venezuala: Soberana-2 was authorized from age 2 in November 2021.
- The proportion of the population under 5 is over 8%.
Summary of results of authorized and other vaccines
Authorized for under-5s in Cuba only.
Abdala is a 3-dose protein subunit vaccine produced by CIBG in Cuba. It’s the only vaccine in use for the under-5s with no results public. Although it was authorized for 2 years up back in October 2021, it’s not clear how much it was used in that age group, with Soberana used so widely.
Results from the 48,000-participant phase 3 trial in adults haven’t been published either. The manufacturer has only released a press release showing 92.3% against symptomatic disease, with no severe disease or deaths in the vaccinated group. There are phase 1/2 results in adults. The WHO has begun evaluating this vaccine.
From what we know, Abdala may be a vaccine with very high efficacy against the original virus, and a low rate of adverse effects. A trial in under-2s is reportedly planned, but I haven’t found a trial registration record for it yet.
I wrote a bit more about this here. Cuba rolled its vaccines out early in the evaluation process because the country was facing a variant-driven surge in May 2021: the small risks of a shortcut with traditional vaccine types were considered worth taking. That wave saw death rates climb higher than in the US at that time – see the graph below. Vaccination of the nation was quick and extensive: at this point, 94% have had at least one vaccine, and most have had a full course, and 63% have had a booster since. Since February, Covid deaths have been remarkably low – I’ve included Japan for comparison. Vaccination isn’t Cuba’s only pandemic response. For example, when another surge began in January this year, testing and vaccine requirements for people coming into the country were re-introduced.
BBIBP-CorV – Sinopharm’s Beijing vaccine
Authorized for under-5s in Argentina, Bahrain, China, and the United Arab Emirates.
BBIBP-CorV is a 2-dose inactivated vaccine developed by Sinopharm’s Beijing Institute of Biological Products (BBIBP). There are 2 Sinopharm inactivated vaccines: this one and another produced by the Wuhan Institute of Biological Products. Sinopharm’s phase 3 trial for adults tested both vaccines. Efficacy for the Beijing vaccine was 78.1% (CI 65-86) against symptomatic disease, with no severe Covid in the vaccinated group.
There are clinical trials running for children from age 3: a phase 1/2 trial, a phase 3 trial, and a phase 4 trial. Results are available for the first of those (phase 1/2). Plus there are community use studies from Argentina and Bahrain.
In the clinical trial report, there are 96 children aged 3-5 in phase 1, and 240 in phase 2. The trial tests 3 different doses, in 3 age groups – 6-12 years and 13-17 as well. Some results are reported separately for each age group. The rate of adverse events was low, and similar to that in studies for adults. Although all children seroconverted, immune responses for the 3-5 year-olds weren’t as strong as for older children.
The community use study in Bahrain was also small, evaluating adverse events and immune responses only from age 3 to 17 – up to about a month after vaccination. There were 93 children under 6 in the adverse events part of the study, and 60 for immune response. The rate of adverse effects was low – the most common reported was fever in 14% of the 3-6 year-olds. Immune response for the children from 6-9 were stronger than the younger and older children.
The vaccine effectiveness study from Argentina is a large one, but it doesn’t break out the data for the under-5s. Vaccination for children aged 3-11 began in October 2021, with a 2-dose course of the Beijing vaccine for immunocompetent children, and a 3-dose one for children with compromised immune systems. (Adolescents got one of the 2 mRNA vaccines, Moderna and Pfizer.)
Argentina was between Covid waves in October, before a major new surge starting in December. The study analyzed Covid-associated hospitalization for children who had 2 doses by the end of November, as well as children who had none. The researchers identified children who were hospitalized within 2 weeks of a Covid diagnosis, from December 14. This was monitored until early March 2022 for children who never tested positive. In December and early January, both Delta and Omicron were circulating: after that, Omicron was dominant.
There were 630,908 vaccinated 3-11 year-olds, and 58,644 unvaccinated. The unvaccinated were a little younger, more likely to be female, and less likely to have co-morbidities. Vaccine effectiveness against hospitalization across the whole time was 76·4% (CI 63-85) for 3-11 year-olds. For the earlier Delta/Omicron period, it was 83·4% (CI 71-90), and in the Omicron wave it was 58·6% (CI 4-80). (For the mRNA-vaxed adolescents, it was around 80% across both periods.)
BNT162b – the Pfizer vaccine
There has been a phase 2 trial of this mRNA vaccine in children from the age of 2, but no results are public for that yet. There are 2 sets of results to look at: the company’s phase 1/2/3 trial from 6 months of age, and the German study of off-label use I mentioned at the top of this post. Let’s start with the phase 1/2/3 trial.
That trial was designed to test out 2 shots of various doses: 3 μg, 10 μg, 20 μg, and the same dose that’s given to adults, 30 μg. In December 2021, the trial was expanded to add a third shot to the 3 μg regimen, at least 2 months after shot 2. The trial was run in Finland, Poland, Spain, and the US. The only results so far are from a press release. As with the Moderna vaccine, though, an FDA evaluation is just around the corner.
There were 1,678 under-5s in the trial getting the 3 very low doses (3 μg), and the trial was running during the Omicron wave. The press release describes immune response as “strong”, and reactions “similar to placebo”. But there are no further details, other than that the 2 primary trial outcomes – geometric mean titer ratio (GMT) and seroconversion rate – met the pre-specified goal: being similar to the results for young people (aged 16 to 25).
Vaccine efficacy was a secondary outcome, but they report that it was high for the Omicron wave: 80.3%. No details of the range of statistical uncertainty were given, and no word on whether anyone developed severe Covid. The implication, though, is that no one did. The press release reports there were “10 symptomatic Covid cases” from 7 days after dose 3, and says that the protocol specifies a formal analysis at 21 cases. There’s no indication of how long they think that will take.
If these results hold as the numbers grow, then this 3-dose course would be at the high end for efficacy and the low end for adverse reactions.
Next up is the study of off-label use in Germany, independent of the vaccine manufacturers. It’s called CoVacU5, and it only focuses on adverse events. The researchers sent emails to all the parents with email addresses of children who had 3-10 μg of the Pfizer vaccine off-label, from newborn to under 5. The sources were databases of 21 outpatient facilities and 2 nation-wide layperson-initiated vaccination programs: U12Schutz (under 12 protection) and Bildung Aber Sicher (aiming to make early education safe from infections).
U12Schutz promotes off-label use for the under-5s, with resources for both doctors and parents. Parents signed up to their database to get notified of where they could get off-label vaccine. Their website says as of February 13, over 15,800 families had signed up. The group estimates that more than 40,000 under-5s have been vaxed off-label.
The CoVacU5 researchers managed to compile 19,000 email addresses, sending out invitations to participate in a web-based survey of reactions to the Covid vaccine and to non-Covid vaccines in the same child. Out of the responses they got, there were 7,924 under-5s with authentication codes. After excluding 69 children who had been vaxed with Moderna off-label, and 49 who had been vaxed before May 2021, they had data for 7,806 children who had at least 1 shot (41% of the original 19,000), most of whom had 2 shots. (A minority had 1 or 3.) Most were between 2 and under 5 years old for their first shot, and had 5 or 10 μg shots (though some had 3 μg).
Close to 8,000 is a lot, but we don’t know if these people’s experience is typical. And a really big weakness here is that the study relies on parents’ memories of reactions to the vaccine, so these results don’t have the same weight as trial data where people have recorded temperature etc in a daily diary. The way that can distort the picture we get is called recall bias.
The rate of children with apparent vaccine adverse reactions requiring hospitalization was 0.1% (10 children) – all of whom had doses of 5 or 10 μg or unknown dosage, not 3 μg.
To reduce the impact of recall bias, the researchers analyzed the responses for Covid and non-Covid vaccines that had been given between January 15 and May 9, 2022. Local reactions around the injection were a bit more common for the Pfizer Covid vax, but general symptoms like fever were a bit less common. They concluded that the reactions to the lower doses of the Covid vax were fairly typical for young children’s vaccination.
When doctors give off-label vaccines in Germany, they are obliged to formally notify any serious adverse events to the vaccine authority. At the end of March 2022, none had been reported for children under 5.
(Note: The statistical analysis plan for the CoVacU5 study is here.)
CoronaVac – Sinovac’s vaccine
Authorized for under-5s in Chile, China, and Hong Kong.
CoronaVac is a 2-dose inactivated vaccine, developed by Sinovac in China. This was the most used Covid vaccine globally as of late 2021. In phase 3 trials for adults, vaccine efficacy ranged from 51% (CI 36-62) to 84% (CI 65-92), with no severe (Grade 4) Covid in the vaccinated groups. Those trials weren’t very large, the populations were very different, and the interval between doses was different as well.
There are 8 clinical trials of CoronaVac in children from age 3, and another from 6 months of age (see this post’s addendum for links). Results are available for 2 of the trials starting at 3 years of age: a phase 1/2 trial in China (with all participants Chinese), and a phase 3 trial in Chile. There is also a study of 27 of under-5s inadvertently given a single dose of CoronaVac in Brazil, and a very large population study of the vaccine’s effectiveness for 3-5 year-olds during the Omicron wave in Chile.
The phase 1/2 trial includes 24 children aged 3-5 in phase 1, and 119 in phase 2. It’s a trial in children and adolescents (up to 17) of 2 different dosages. The overall rate of adverse events was very low – less than 5% for each systemic event like fever. Those results weren’t broken down by age group, but immune response data was reported for the 3-5 year-olds. All seroconverted, and immune responses for the younger children were higher than for adolescents – overall, response was similar to adults in other studies.
The phase 3 trial in Chile includes 873 children aged 3-11, as well as adolescents. Although results are provided for the 3-11 year-olds, they aren’t broken down further. The rate of systemic adverse effects was a bit higher than the phase 1/2 trial, but still low: the most common was fever, at 9% after the first dose. Immune response was higher in the young children and adolescents than it was in adults in another study by the same authors.
The vaccine effectiveness study analyzed the outcomes for the whole population of 3-5 year-olds in the national public healthcare system, during Chile’s Omicron wave from December 2021 to the end of February 2022. There were 516,250 children in this age group in the system, and 25,556 were excluded from the analysis because they had either had Covid or a dose of vaccine before December 6. Of the remaining population of 490,694, most had received 1 or 2 doses (194,427 had 2), and 189,523 were still unvaccinated. In the study period, 3% had laboratory-confirmed Covid, and 2 died (both of them unvaccinated).
The analyses here were adjusted for age, sex, region of residence and a proxy of household income, nationality, and whether the child had a condition that may increase the risk of severe Covid. Vaccine effectiveness in the Omicron wave from 14 days after the second dose was:
- Against Covid: 38.2% (CI 37-40)
- Against hospitalization: 64.6% (CI 50-75)
- Against intensive care for Covid: 69.0% (CI 19-88)
Covaxin (BBV152) is an inactivated vaccine developed by the Indian Council of Medical Research and Bharat Biotech. In the vaccine’s phase 3 trial with around 25,000 adults, vaccine efficacy was 77·8% (CI 65-86). Like the other inactivated Covid vaccines, the rate of adverse events was very low. It was authorized for use from age 6 in late April 2022.
In March this year, the WHO suspended use of this vaccine because of concerns about manufacturing quality.
Adverse effects and immune response have been studied a in phase 2/3 trial for 526 children and adolescents, split between 3 age groups: less than 6, 6 to less than 12, and 12 to 18. The dose was the same as for adults. There were no major differences in response or reaction between the 3 age groups – seroconversion rates were 95-98%. Antibody responses were stronger than adults in the other studies for this vaccine.
The participants in this trial were all in India.
The only results available for this mRNA vaccine so far come from a press release. An evaluation report from the FDA is just around the corner though. There are 6,700 participants from 6 months to under 6 years of age in the phase 2/3 trial for this vaccine: 5-year-olds aren’t reported separately. The dose for was 25 μg – half the dose given to 6-12 year-olds (50 μg), and a quarter the amount for adults (100 μg). The trial participants were all from the US.
This trial aimed to assess adverse events as well as signs of immune response: both were similar to the rates in young adults (aged 18-25), which puts it at the high end for Covid vaccines. The rate of fever was “consistent with other commonly used and recommended pediatric vaccines”, according to the press release. At 17% for the 6 months to under 2 years group, and 15% in the 2 to under-6s, it was lower than the rate for the 6 to under-12s (who get a higher dose).
Vaccine efficacy was secondary in the trial design. It was running during the Omicron wave. The wording of the press release is a bit ambiguous: while it’s clear that there were no severely ill or hospitalized children in the vaccinated group, and it sounds like there weren’t in the placebo group either, but I can’t be sure. For mild Covid, vaccine efficacy was 43.7% in the infants from 6 months to 2 years group, and 37.5% from 2 to under 6. (They don’t report the CI range, except to say they both start above 0.) We really need to see more data here. The company’s press release states that this “was consistent with the lower two-dose effectiveness against Omicron seen in adults”. It’s not clear to me what they are comparing to, given that waning was also generally a complicator for double-dosed adults when the Omicron wave arrived. (See for example this study from the UK.)
Soberana-2 and Soberana-Plus
Authorized for under-5s in Cuba and Venezuela (Soberana-2 only).
This is another 3-dose course, with 2 doses of Soberana-2 and the third, Soberana-Plus. These are both protein subunit vaccines. Soberana-2 is a conjugate vaccine – the SARS-CoV-2 component is joined with tetanus toxoid to increase its potency. They were developed by Cuba’s Finlay Institute of Vaccines (IFV). The full course is used from aged 2 up in Cuba – unless the child has already had confirmed Covid: then they get a single shot of Soberana-Plus.
The 44,000+-participant phase 3 trial for the 3-dose course in adults was run in Cuba while the Beta variant was giving way to Delta. Vaccine efficacy was 92.4% (CI 87–96), with no severe Covid in the vaccinated group. A phase 3 trial for 24,000 adults in Iran during a Delta wave reportedly had 67% efficacy against symptomatic disease, and vaccine efficacy of 97% against severe Covid and Covid-related hospitalization. It’s a high-efficacy vaccine with a low rate of adverse effects.
There are 2 trials of the 3-dose course in children from age 3: a phase 1/2 trial, and a phase 2 trial. And there’s a phase 1/2 trial of single-shot Soberana-Plus in children who recovered from Covid. Results have been published for the first of these trials only. That trial assessed adverse effects and immune response only, and included 25 children aged 3-11 in phase 1, and 150 in phase 2. Immune response was non-inferior (similar) to that of young adults, and the rate of adverse reactions was low – only 3% had systemic adverse event (general symptoms like fever).
Cuba rolled its vaccines out earlier in the evaluation process than normally, because of a major surge of Covid, achieving high vaccination coverage very quickly. The results were dramatic. There’s more about this in the Abdala section above.
Other vaccines in trials for under-5s
Another 5 Covid vaccines are in trials with under-5s, but results aren’t publicly available as far as I know. (Note – the links below are to the records in my collection for all their trials tagged for children and adolescents.)
- KCONVAC (inactivated vaccine from Shenzhen Kangtai Bio, China) – aged 3+
- SCB-2019 (protein subunit vaccine from Clover Biopharmaceuticals, China/Australia) – aged 2+
- WIBP (Wuhan) (inactivated vaccine from Sinopharm, China) – aged 3+
- VLA2001 (inactivated vaccine from Valneva, France) – aged 2+
- Zifivax (ZF2001) (protein subunit vaccine from China) – aged 3+
Addendum: Covid vaccines with results from studies with children under 6
* Vaccine is authorized for use in at least one country
** In the results column, “for” means results in the under-5s (or under-6s) reported, “include” means the outcomes for under-5s are not reported separately
|Study details||Results including children under 5|
|Phase 1/2 trial|
(include 96 aged 3-5 in phase 1, 240 in phase 2 – some outcomes reported separately by age group)
|Phase 3 trial|
|Phase 4 trial|
|Community use study:|
Vaccine effectiveness in during Omicron outbreak in Argentina
(for age group 3-11 only: 630,908 vaxed + 58,644 unvaxed)
|Community use study:|
Adverse effects and immune responses in Bahrain
(include 93 aged under 6 for adverse effects, 60 for immune response)
|BNT162b – Pfizer vax|
|Phase 2 trial|
|Phase 1/2/3 trial|
Aged 6 months+
(for 1,678 under 5)
|Community use study:|
Short-term adverse effects in off-label use in Germany
(for 7,806 under 5)
|Phase 1/2 trial|
(includes 24 aged 3-5 in phase 1, 119 in phase 2)
|Phase 2b trial|
|Phase 3 trial|
Aged 6 months+
|Phase 3 trial (Chile)|
(includes 873 aged 3-11)
|Phase 3 trial (comparing to Pfizer)|
|Phase 4 trial|
|Phase 4 trial|
|Phase 4 trial – co-administered with enterovirus 71 vax|
|Lot-to-lot consistency (trial)|
|Community use study:|
Vaccine effectiveness during Omicron outbreak in Chile
(for population of 490,694 children aged 3-5)
|Community use study:|
Adverse effects and immune response in children inadvertently vaccinated in Brazil
Aged 7 months-5 years
(for 27 aged up to 5)
|Phase 2/3 trial|
(for 175 aged 2-6)
|Phase 2/3 trial|
Aged 6 months to less than 12
(for ~6,700 aged under 6)
(2 doses Soberana, 1 dose Soberana-Plus)
|Phase 1/2 trial|
(for 25 aged 3-11 for phase 1, 150 for phase 2)
|Phase 2 trial|
|*Soberana-Plus (1 dose)|
|Phase 1/2 trial|
Aged 2+ (recovered from Covid-19)
Disclosures: My interest in Covid-19 vaccine trials is as a person worried about the virus, as my son is immunocompromised: I have no financial or professional interest in the vaccines. I have worked for an institute of the NIH in the past, but not the one working on vaccines (NIAID). More about me.