Analyzing results from Johnson & Johnson: Why the results are better than you think.

The Johnson and Johnson/Janssen vaccine was just given emergency use approval by the FDA this weekend based on a phase 3 study called ENSEMBLE. Here is the FDA report and protocol with all of the details of the clinical trial and its results. In this blog post, I will summarize how this vaccine differs from the other two, Moderna and Pfizer/BioNTech, given emergency approval by the FDA in the USA so far, and summarize results from the phase 3 trial.

The overall results showed 66.5% efficacy in preventing symptomatic disease, with some evidence for protection against asymptomatic disease, hospitalization and death, and the safety profile was very good with serious adverse events and deaths no higher in the vaccine group than in the saline placebo group.

With the overall vaccine efficacy for preventing symptomatic disease only 66.5% relative to the 95% and 94.1% for Pfizer/BioNTech and Moderna vaccines, many will wonder why anyone would want to get the Johnson and Johnson vaccine instead of these other two. I will address this, and outline why I believe that this Johnson and Johnson vaccine may be just as good or better than the other two, or at least close enough that I would gladly take the Johnson and Johnson vaccine if that is the one I was offered. In most cases, people will not have a choice but will have to decided whether or not to accept the one that is offered.

Here are my main points, with the rest of the post providing details and support:

• Distribution is much easier, with only a single dose required and the vaccine only requiring refrigeration, not deep freezing

• The vaccine's efficacy after a single dose seems competitive with or maybe even better than the single dose results for competitors based on available data.

• Unlike the competitors tested before their emergence, this vaccine demonstrates efficacy against the variants with the problematic "immune escape" mutations (e.g. South African B.1.351) without the need for an additional booster.

• Like the competitors, the rates of serious adverse events in the vaccinated group is no higher than the saline placebo groups, but this vaccine appears to have milder transient side effects like pain and swelling at injection site, fever, chills, headache, fatigue, and nausea, so may be more comfortable to receive.

• After results from a separate two-dose trial that should complete shortly, it is possible that a second dose will be later added that could increase the efficacy to be equivalent or even better than the competitors.

• This vaccine uses a different technology than the mRNA vaccines, so it might be a good choice for individuals uncomfortable with the mRNA technology for whatever reason. It also does not contain PEG so is not likely to have concerns about the rare but potentially dangerous anaphylactic reactions seen from some on the mRNA vaccines.

Overview of vaccine

The vaccine developed by Johnson and Johnson is what is called a viral vector vaccine, Like the Moderna, it involves using some portion of the genetic code that is specific to the SARS-CoV-2 spike protein to generate the immune response, but instead of the mRNA vaccines that take mRNA sequences that are encased in lipid nanoparticles to protect them, in viral vector vaccines DNA matching the viral sequence are injected into another virus that serves as the "vector" or vehicle of delivery to the cell, sort of a "Trojan horse" to get the spike protein genetic code into your cells to induce the immune response. The viral vector has been deactivated so it can't replicate or make you sick. The AstraZeneca/Oxford vaccine uses a chimpanzee adenovirus vector (common cold), while Johnson and Johnson use a human adenovirus (common cold) called Ad26 as the vector, and the Russian Sputnik V vaccine uses a two dose sequence for which the first uses the same Ad26 viral vector and the second uses an alternative Ad5 human adenovirus vector.

One key advantage of this strategy is that DNA is less fragile than mRNA, and so this vaccine does not require the deep freeze storage of the mRNA vaccines, only mild refrigeration, and so is logistically much easier to distribute.

It also does not contain Polyethylene Glycol (PEG), which is thought to be behind the rare but potentially dangerous anaphylactic reaction experienced by some after the mRNA vaccines.

Also, this EUA and the phase 3 trial upon which it was based only involved a single dose of the vaccine, not requiring a second injection. This also makes distribution much more convenient, and as I will explain later, opens the opportunity to later add a second booster injection that may further increase efficacy once the ENSEMBLE 2 clinical trial looking at two-dose efficacy is complete, which could potentially bring overall efficacy levels up to what was seen for the mRNA vaccines.

Overview of trial

This trial was a double-blind, randomized, placebo-controlled trial in which the participants were randomized to receive either a single dose of the vaccine or a single dose of a saline placebo. The double-blinding means that neither the participant nor the treating physicians nor study leaders had any idea who was given vaccine or placebo until the end of the study, which protects study integrity and ensures that the difference between vaccine and placebo groups provides an unbiased estimate of the causal effect of the vaccine.

The study included almost 44,000 participants, with 21,895 given vaccine and 21,888 given placebo, and with >1/3 over 60 years in age, and ~1/4 having comorbidities, and with 7% Black and 30% Latino. It was conducted in three regions, with 44% in the USA, 15% in South Africa, and the remaining 41% in Latin America, including 16.6% from Brazil.

Participants were given PCR and serology tests at baseline to assess whether they were currently or previously infected with SARS-CoV-2, and 2233 (10.2%) of vaccinated and 2166 (9.9%) were previously infected with SARS-CoV-2. These were analyzed separately from the group of subjects not previously infected as I will later detail.

The primary endpoint was efficacy in preventing moderate or severe PCR positive COVID-19 starting 28 days after vaccination, defined as % reduction in symptomatic infection rate in thef vaccine relative to the placebo. Given uneven sample size and follow up times, the efficacy was computed by comparing the infection rate for placebo and vaccine, with infection rate for placebo defined as number of moderate/severe PCR positive cases after 28 days divided by the total number of person-years of exposure for subjects in the placebo group, and likewise or the vaccinated group.

If anyone reported symptoms specified in the protocol as indicating potential moderate or severe disease, they were given a PCR test to assess whether they were SARS-CoV-2 positive, and if so they were counted as a moderate/severe COVID-19 case. The primary difference between this criterion and the "symptomatic COVID-19" criterion used in the other vaccine trials that also includes mild disease is that moderate/severe disease omits those with only one minor symptom, such as fever, cough, or headache, while the full symptomatic disease endpoint includes anyone reporting any of those symptoms along with a positive PCR test.

Another distinction in this trial is that they gave antigen tests to test for asyptomatic infection on days 1, 29, and 71, so they could also get some data on whether the vaccine protects against asymptomatic infection.

Trial results: Efficacy

For the primary endpoint, they found that the overall efficacy vs. moderate/severe disease from day 28+ after vaccination was 66.1%, with 114 moderate or severe cases in the vaccine arm and 326 in the placebo arm, with similar results for those over (66.2%) or under (66.1%) 60 years old. The efficacy was 66.5% vs. symptomatic disease if mild cases were also included in the numbers.

Here is a plot of infections over time, showing that the protection of the vaccine kicks in about day 14 after vaccination, and substantially reduces the number of moderate or severe COVID-19 cases.

This trial was conducted after the "immune escape" variants that appear to evade immune response emerged in South Africa and Brazil, so they split out efficacy results by region as well, finding the efficacy against moderate/severe disease was 72.0% in the USA, 68.1% in Brazil, and 64.0% in South Africa. This demonstrate that the vaccine appeared effective against the variants predominant in these countries, albeit at a perhaps slightly lower level of efficacy (5-10% decrease).

Here are some other secondary efficacy analyses:

• Severe Disease: Focusing on severe/critical disease only, the overall estimated efficacy was 85.4% (5 cases for vaccine vs. 34 for placebo), with 85.9% in the USA (1 vaccine/7 placebo), 81.7% in South Africa (4 vaccine/22 placebo), and 87.6% in Brazil (1 vaccine/8 placebo). This is promising but the sample sizes are small.

• Hospitalization: Only 16 with positive PCR tests required hospitalization, and all were in placebo group. Also promising but small sample size.

• COVID-19 Deaths: There were only 7 COVID-related deaths, and all occurred in placebo subjects, and all in South Africa. Promising but small sample size.

• All Cause Mortality: Overall 19 participants died during the trial for any reason, and 16 were in placebo arm, and only 3 in the vaccine arm, corresponding to an 81.3% efficacy in preventing all cause death.

• Asymptomatic Cases: A total of 37 placebo and 10 vaccine subjects demonstrated SARS-CoV-2 antibodies after 29 days without having reported symptoms, suggesting an estimated 74.2% efficacy vs asymptomatic disease.

• Previously Infected Cohort: Out of the previously infected cohort of 2122 in vaccine and 2030 in placebo, there were 4 moderate/severe cases in the placebo arm and 3 moderate/severe cases in the vaccine arm. This corresponds to an efficacy estimate of 28.5% but the data is so scare the 95% confidence interval is (-322.8%, 89.5%) so there is very little data on this.

• How protective is previous infection? This was not reported in the protocol, but looking at the reduction in rate of moderate to severe infection across all placebo subjects in Table 14, we find 4 events out of 320.8 person-years for those who were previously infected, and 509 events in 3409.8 person-years for those who were not previously infected before the trial. This corresponds to 92.4% efficacy of "previous infection", and indicates that those previously infected were quite protected against reinfection whether given vaccine or not. Those previously infected who were given vaccine had 3 events out of 336.3 person years, providing an estimated 94.6% efficacy for those vaccinated with previous infection vs. those given placebo without previous infection.

Trial results: Safety

The safety results are overall very good. Here is a summary of some of the key points:

• Serious Adverse Events: Serious adverse event (SAE) rates were similar in both vaccine and placebo arm, with 0.4% of vaccine participants (83/21,895) and 0.4% of placebo participants (96/21,888) reporting SAE

• Deaths: Total deaths were much lower in vaccine arm (3/21,895) than placebo arm (16/21,888), which includes 6 confirmed COVID-19 deaths.

• Local adverse events: There were certain local adverse events (i.e. pain in injection site) that were solicited by the study leaders and these occurred in 50.2% of vaccinated and 19.4% of placebo subjects. Only 0.7% of vaccinated or 0.2% of placebo subjects experienced grade 3 local adverse events, which means they could not perform their daily duties, but all resolved quickly. The most common was pain in the injection site which was reported in 48.6% of vaccinated and 16.7% placebo subjects.

• Systemic adverse events: There were certain systemic adverse events (fever, headache, fatigue, nausea) that were solicited by the study leaders and occurred in 55.1% of vaccinated and 35.1% of placebo subjects. Only 1.8% of vaccinated and 0.6% of placebo subjects experienced grade 3 systemic adverse events, and all resolved. The most common were headache (38.9% vaccine vs. 23.7% placebo), fatigue (38.2% vaccine vs. 21.5% placebo), nausea (14.2% vaccine vs. 9.2% placebo), and chills (9.0% vaccine vs. 0.6% placebo).

• Unsolicited adverse events: Additionally, 13.1% of vaccinated and 12.0% of placebo subjects reported unsolicited adverse events, with 1.4% of vaccinated and 1.9% of placebo subjects reporting events requiring medical attention, and 0.6% of vaccinated and 0.6% of placebo subjects being grade 3 events.

• Potential concern of clotting: Overall, there were 15 thromboembolic events in the vaccine and 10 in the placebo arms, including 5 cases of thrombosis (clotting) in the vaccine arm and 2 in placebo arm, and 4 cases of pulmonary embolism in vaccine arm and 1 in placebo arm. Although low prevalence and not enough evidence to conclude these differences are statistically significant, the fact that they are serious and higher in the vaccine arm suggests these are serious adverse events that need to be carefully monitored.

Why would I take Johnson and Johnson if efficacy from phase 3 trial is lower?

A natural first thought when seeing these results is, "Why would I consider taking a vaccine with only 66% efficacy when there are others with 95% efficacy?" I had this thought myself. Upon more careful assessment, however, the Johnson and Johnson results are better than they may appear, for the following reasons:

1. This efficacy is comparable to single dose efficacy of competitors

Remember that this study assesses efficacy after a single dose, while the others only looked at efficacy after two doses. However, we have accruing data about single-dose efficacy from the competitors:

• The FDA report for the Pfizer vaccine reports results about efficacy after dose 1 but before dose 2 (Table 13, page 32), and finds an efficacy of 52.4%, with 90.5% efficacy in the first 7 days after dose 2 and 94.8% efficacy starting 7 days after dose 2.

• A preprint in the Lancet reporting results from the SIREN study of UK health care workers who have been vaccinated with the Pfizer vaccine or not report 72% efficacy starting 14 days after dose 1 and 86% starting 7 days after dose 2 after adjustment for covariates.

• A peer-reviewed publication in the New England Journal of Medicine reports results comparing those vaccinated with the Pfizer vaccine vs. not from Israel, and reports 46% efficacy on days 14-21 and 60% from days 21-27 after vaccination with the first dose, and 92% starting 7 days after the second dose.

• A peer-reviewed publication in the Lancet reports results from the phase 3 trial comparing placebo to two-dose Russian vaccine Sputnik V. This vaccine, like Johnson and Johnson, uses a viral vector approach, and the first dose in fact uses the exact same human adenovirus as the vector (Ad26), while the second dose uses an alternative human adenovirus vector (Ad5). Their data demonstrate a single-dose efficacy of 72.8% from days 14-21 after first dose, and 91.6% efficacy after second dose.

Thus, we see that in context, 66.1% single-dose accuracy is not so bad. It appears competitive or even better that the single dose efficacy of Pfizer based on the limited data we have on efficacy between first and second dose, and it is close to the 72.8% efficacy after first dose seen by Sputnik after the first dose which happens to be a viral vector vaccine using the exact same human viral vector as the Johnson and Johnson.

The fact that Pfizer had 95% efficacy after second dose and Sputnik 91.6% efficacy after second dose suggests that the two-dose Johnson and Johnson vaccine may have >90% efficacy like the competitors. This is further supported by analyses relating efficacy to neutralizing antibody titers for the various vaccines in this report, with the figure presented below showing the relationship that follows a predictable curve. Note the single dose JnJ (Ad26.COV2.S) has 66% efficacy and neutralizing antibody titers 0.5 times the level of convalescent plasma, while the two-dose Sputnik V (rAd26-S+rAd5-S) has efficacy of 92% and neutralizing antibody titers 1.5x convalescent plasma, and Pfizer/BioNTech (BNT162b2) has 95% accuracy and neutralizing antibody titers of 2.5x convalescent plasma.

The following tweet responding to my question about how two dose JnJ does, researchers have generated some data from the 2-dose JnJ vaccine, demonstrating neutralizing antibody titres of 2.4x convalescent plasma, similar to Pfizer/BioNTech and Sputnik V, which suggests >90% accuracy according to the relationship above.

2. It will be easy to get a booster containing a second dose of the Johnson and Johnson vaccine once a separate two-dose phase 3 trial is complete potentially providing full two-dose efficacy on par with Moderna or Pfizer/BioNTech

In November, Johnson and Johnson commenced a two-dose phase 3 clinical trial ENSEMBLE 2 whose protocol is publicly available that randomized 30,000 participants to placebo or two doses of the vaccine with doses spaced 8 weeks apart. This trial will provide rigorous data about two-dose efficacy for this vaccine that might be more competitive with the mRNA competitors.

If this trial shows even greater efficacy than the single dose shot, then the FDA can give EUA to the two dose regimen and it will be easy to get individuals who received the first dose already to come in and get the booster so they can achieve the full two-dose efficacy. Given that supply limitations have caused many delays in second dose injections for many with the Moderna and Pfizer/BioNTech vaccines anyway, many are currently walking around with only the lower single dose efficacy anyway.

3. The Johnson and Johnson vaccines show efficacy against new South African and Brazilian variants that were not in the studies for Moderna or Pfizer/BioNTech

In late fall 2020, a viral variant names B.1.351 emerged in South Africa and quickly overtook all other variants to comprise nearly all new infections in that country. It has one mutation called E484K is considered an "immune escape" mutation meaning that it helps the virus evade immunity caused by previous infection and can make vaccines less effective. Similarly, viral variants named P.1 and P.2 have emerged in Brazil that contains this same E484K mutation. This mutation has also been detected in some sequenced viruses in the USA recently, especially in New York, and since the USA is doing very little sequencing it is possible that it may be more prevalent in the USA than we realize.

The Moderna and Pfizer/BioNTech phase 3 studies were enrolled in late summer and early fall before these variants appeared, and their trials did not include any subjects who were exposed to and infected with these new viral variants, and also were focused in North America so did not have Brazilian or South African subjects.

This phase 3 trial for Johnson and Johnson was international, including 15% of subjects from South Africa and 16.6% from Brazil, and accrued after these variants already had emerged and become predominant. In the study, 94.5% of those sequenced in the South African cohort had the B.1.351 variant, and 69.4% of those sequenced in Brazil carry the P.2 variant.

As mentioned above, the efficacy was found to be 66.1% overall, but 72% in the USA, 64% in South Africa, and 68.1% in Brazil. This suggest this vaccine works quite well on these "immune escape" variants, and might not require an additional booster.

Recent studies have found that neutralizing antibody levels for Moderna are 6-fold lower in the South African B.1.351 variant, and for Pfizer, 3-fold lower. There is no firm data on how this affects the corresponding efficacy, but based on the link above modeling the relationship of neutralizing antibody levels and efficacy, such a 3-6x reduction would correspond to 0.4x-0.8x convalescent plasma, which based on the plot above suggest the efficacy for two dose Pfizer or Moderna against this variant would be somewhere around 66-78%, which is not much better than what we see for the Johnson and Johnson single dose. Both companies are devising a booster for this variant that would amount to a third shot once approved, and are likely to improve on this variant-specific accuracy. But it is plausible that the Johnson and Johnson is at least competitive with the current Moderna and Pfizer vaccines in terms of efficacy vs. the immune escape variants.

4. Potentially fewer immediate side effects after vaccination

While the Moderna, Pfizer/BioNTech, and Johnson and Johnson all appear generally safe given rates of serious adverse events and deaths no higher than placebo, it appears that the Johnson and Johnson vaccine may have milder short term side effects just after injection, which might make them more comfortable to receive.

Although not dangerous, these short-term side effects occurring just after injection including pain and swelling at the injection site, headache, fever and chills, fatigue and nausea are painful, inconvenient, and for some people cause them to miss work or other activities for a few days. The rate and severity of these side effects appear to be lower for the Johnson and Johnson vaccine based on the studies.

From the data in the FDA reports, we can see that the percent reporting solicited local side effects like pain or swelling in the injection site is 88.6% Moderna, 78.6% for Pfizer, but only 50.2% for Johnson and Johnson. For Johnson and Johnson, only 0.7% of these were grade 3, meaning they would be severe enough to interfere with daily activities.

The solicited systemic side effects including headache, fever and chills, fatigue, and nausea are also slightly lower in Johnson and Johnson, with 55.1% reporting them while Moderna and Pfizer have 77.6% and 59.1%, respectively, reporting such symptoms. For Johnson and Johnson, only 1.8% are reported as grade 3, meaning they would be severe enough to interfere with daily activities.

5. Some might be more comfortable with the viral vector technology of the Johnson and Johnson vaccine than the mRNA technologies underlying the Moderna and Pfizer/BioNTech vaccines.

While the mRNA vaccines have been shown to be effective and safe in the phase 3 trials and their effectiveness is further validated in reports from population studies that have already been published, some people are uncomfortable with the idea of the mRNA technology either (1) based on the fact that before now it was never previously been used clinically as a vaccine or (2) based on their perceptions of how it works, which is problematic given the many false rumors circulating on social media making erroneous statements about how they work.

One verified concern has been the rare but potentially dangerous anaphylactic reaction to the vaccine that is thought to be from PEG in the vaccine. The Johnson and Johnson vaccine does not have PEG so is it unlikely to have this same reaction.

The Johnson and Johnson vaccine provides an alternative for those who for whatever reason are uncomfortable with the mRNA vaccines.

6. Don't let the perfect be the enemy of the good: the speed of dissemination is more important than getting a few extra % of efficacy.

The vaccines provide two types of benefits to the recipients:

• Direct benefit of reduced chance of infection and if exposed to the virus, and likely less severe disease if infected

• Indirect benefit of reduced chance of exposure to the virus if enough of the population is vaccinated.

People primarily focus on the first direct benefit, but in fact it is the second indirect benefit that is more substantial. As a higher proportion of the population is vaccinated with even a slightly less effective vaccine, this will substantially slow the spread of the virus and eventually will get to a point where the virus is strongly declining in the population enough that exposure becomes rare. At this point, the fact that the vaccine is not 100% effective if exposed is not as important since the chance of being exposed is so much lower. This is important to keep in mind.

Conclusion

Thus, in conclusion, the Johnson and Johnson results are much better than they first appear. We know the vaccine is much easier to handle, only requiring refrigeration, not deep freeze. The vaccine's efficacy after a single dose seems competitive with the single dose results for competitors, the short term side effects seem more mild, and the vaccine appears effective against the emerging variants without a booster shot necessary.

After results from a separate two-dose trial that should complete shortly, it is possible that a second dose will be later added that could increase the efficacy to be equivalent or event better than the mRNA vaccines. They were smart in getting the single dose regimen approved first, so they can get started vaccinating without holding back second doses, and by the time the second trial is done, they can easily have people return for a second dose to boost their immune response if the data suggest it is beneficial. But they have scientific and regulatory justification to start the single-dose distribution.

The fact that the other vaccines were only studied as two-dose regimen makes it controversial to try to delay the second dose even if most of the benefit is secured by the first dose and supply concerns limit the ability to give second doses on time.

It is certainly a viable choice, and if offered I would take it without hesitation.