Malaria Vaccine Success? Not If You Look at Adverse Effects!

Before accepting claims of a vaccine’s efficacy, it’s wise to look at the study and who financed it. A new study for a malaria vaccine is a case in point. It was financed by the manufacturer and the lead researcher is a co-patent holder! It should come as no suprise that there are gaping flaws in the study, as discussed here.

by Heidi Stevenson

A new study claims a never-before seen efficacy rate of 72% for a new malaria vaccine. The researchers have drawn the attention of the Bill Gates Foundation, which may give them $100 million in funding to try to bring it to market. But have they really achieved such a result?

At first glance, it seems likely that this study is valid. They did something rather unusual in today’s vaccine-hyped world: They used a real placebo, a saline solution, in their control group. That, though, is not the only thing that must be assured. Before discussing problems with this study, let’s first take a look at an outline of how it was done along with its results.

Note: If you’d like to skip the study summary, and go straight to the critique, click here.

The Study

The study was set in Africa and done in two stages. The tested vaccine was labeled BK-SE (also referred to as BK-SE36). Doses of 1.0 milliliter and 0.5 milliliter were trialed on the children, but only the larger dose was trialed on adults.

Stage 1

Stage 1 used healthy adults aged 21-40. After screening 100 people primarily for health, 56 were accepted into the study. Subjects were tested for serum levels of the specific malaria antibodies for the variety of malaria endemic in the area of the study. They were divided as follows:

• Seropositive:
  • 18 injected with 2 doses of BK-SE1.0.
  • 10 injected with 2 doses of saline. One discontinued because of pregnancy.
• Seronegative:
  • 18 injected with 2 doses of BK-SE1.0.
  • 10 injected with 2 doses of saline.

The results on day 82 were:

• Seropositive at beginning of study:
  • 13 tested positive for malaria antibodies.
  • 10 tested negative for malaria antibodies.
• Seronegative at beginning of study:
  • 13 tested positive for malaria antibodies.
  • 9 tested negative for malaria antibodies.

Stage 2

Stage 2 was done on children and young adults. It was similar to Stage 1, but had two major distinctions:

• No testing was done to determine serum levels of antibodies. It assumed that they were all seronegative. The authors wrote, “[O]ur earlier studies showed that most individuals below 20 years were seronegative.”
• They tested two concentrations of the vaccine, one at half the antigen level of the other.

150 potential subjects were screened primarily for health. 84 were accepted into the study. They were divided as follows:

• 16-20 years old:
  • 11 injected with 2 doses of BK-SE1.0.
  • 11 injected with 2 doses of BK-SE0.5.
  • 6 injected with 2 doses of saline. One discontinued because of pregnancy.
• 11-15 years old:
  • 11 injected with 2 doses of BK-SE1.0.
  • 11 injected with 2 doses of BK-SE0.5.
  • 6 injected with 2 doses of saline.
• 6-10 years old:
  • 11 injected with 2 doses of BK-SE1.0.
  • 11 injected with 2 doses of BK-SE0.5.
  • 6 injected with 2 doses of saline.

The results on day 82 were:

• 16-20 years old:
  • BK-SE1.0: 11 seropositive.
  • BK-SE0.5: 7 seropositive.
  • Saline: 5 seropositive.
• 11-15 years old:
  • BK-SE1.0: 7 seropositive.
  • BK-SE0.5: 9 seropositive.
  • Saline: 6 seropositive.
• 6-10 years old:
  • BK-SE1.0: 10 seropositive.
  • BK-SE0.5: 9 seropositive.
  • Saline: 5 seropositive.

A one-year follow-up was done that included 69 of the 83 children and young adults who completed the Stage 2 trial. They were compared with 50 age-matched controls. These controls were not selected at the same time as the study participants, so they were not examined during the earliest 2 or 3 months of the screening. These results were:

• Saline controls: 2 had malaria.
• Age-matched controls: 9 malaria cases.
• Vaccinated: 0 malaria cases.

Adverse Effects

The primary purpose of the study was not to discover efficacy, but to investigate safety. Reporting mostly on efficacy, the secondary end point, rather than safety, is premature. However, as we’ll see, even the reports of safety are wildly exaggerated.

One 21-year-old was hospitalized for acute bacterial gastritis after vaccination. The authors stated that it was “unlikely related to vaccination”. They reported that he “admitted” taking metronidazole on the day of the vaccination. Why this should be considered mitigating, as the study seems to imply, is mysterious. The drug is given for malaria and can cause severe, even deadly, adverse effects. However, it is not known to cause gastritis. It is, in fact, used as a gastritis treatment.

There were significant numbers of less severe adverse effects (AEs). The authors state:

Most AEs were common/similar across treatments groups and considered not related to BK-SE36 vaccine. Upper respiratory tract infection was the most frequently recorded besides malaria.

Let’s examine this statement. First, the suggestion that most AEs were “considered not related to BK-SE36 vaccine” sounds quite similar to what doctors routinely tell parents who note adverse effects after their children’s vaccinations: “It’s just a coincidence.”

That simply is not an acceptable statement, especially in light of the fact that doctors are all too willing to claim the credit for any benefits seen from any of their treatments, and also tend to dismiss claims of adverse effects from prescribed drugs unless the symptoms described are already accepted as typical.

Now, let’s take a look at just the mild adverse effects:

How, exactly, can they justify the claim that most adverse effects were not associated with the vaccine? Look at the first few and you can readily see that the majority of people who received the vaccine were affected, while hardly any of those who got the saline solution were. Among adults, it was only in blood pressure increase (5:6) that the saline group exceeded the vaccine group—and it’s the item where the two were closest. Among children, only the headache result (0:0:1) was greater in the saline group.

Clearly, mild adverse reactions occurred far more often in those who received the actual vaccine.

Now, let’s look at more serious concerns. Malaria is a gastrointestinal disease. It does not produce respiratory symptoms. Traditional weakened live vaccine antigens, as are used in the BK-SE vaccine, are expected to produce a mild version of the disease. They should not, however, produce symptoms of a different disease, as it would present an additional danger to the subject.

The following table shows adverse effects that were experienced by at least 10% of the subjects:

You can ignore the reported results for malaria. Any positive blood smear was labeled as malaria and is, therefore, meaningless to us. However, the rest of the results are more significant. Notice that:

• 9 (25%) of the adults (Stage 1 study) who got the vaccine experienced upper respiratory tract infections, while only 4 (20%) who got placebo (saline) did.
• 19 (28.8%) of the children and young adults (Stage 2 study) who got the vaccine experienced upper respiratory tract infections, while only 3 (16.7%) who got placebo (saline) did.

Apparently, the researchers didn’t consider this to be significant. However, when you consider the relatively small size of this study compared with the millions who would be vaccinated if BK-SE were approved, the seriousness of these results becomes quite apparent.

Let’s say that one million children receive this vaccine. Then, if the adverse effects occur at the same rate, an extra 127,000 children would suffer from upper respiratory tract infections. Since the targeted population is poor, that means many would not be healthy enough to manage it, and some would likely die. Add to that the gastritis case that occurred in the trial, and you’d have more than 25,000 people who’d suffer severe gastritis.

Then, consider that studies like these, because of their small size, generally do not come even close to finding the true rate of adverse effects. There can be little doubt that this vaccine would probably result in an enormous amount of harm.

Efficacy?

The authors claim that the vaccine reduces malaria infections by 72%, which is far greater than any previous malaria vaccine has been able to accomplish. That sounds quite impressive, but just how realistic is it? They wrote that they did not test the children for antibodies because earlier work had demonstrated that very few children had developed them. That’s an intriguing statement.

Children Were Untested for Malaria on Trial Entry

First, it should be noted that we do not know if subjects in the saline-placebo group had contracted malaria before the study. The omission of seroconversion testing makes it impossible to know, leaving the study’s legitmacy in question.

Second, it seems rather strange to suggest that children and young adults will not have had malaria—and then, at an arbitrary age 20-21 cut-off, assume that people drawn from the same location are likely to have contracted the disease, so require seroconversion testing.

It is, at best, a huge leap of faith to accept that suggestion. Worse, evidence contradicts any claim that children and young adults are unlikely to have had malaria in that region.

Thus, there is no reason to believe that children who were in the saline control group were free of malaria at the start of the study, so these results are, at best inconclusive.

Post-Study Control Group

The post-study so-called control group had 9 cases of malaria, has compared to 0 in the vaccinated group and 2 in the saline group. There is, though, a major problem with this portion of the trial. A significant rule of setting up control groups is that they be equivalent. However, in this study, they were not. The authors wrote:

There was a delay in obtaining ethical approval for the start of the follow-up period and thus recruitment of additional control group only took place during Jan-Feb 2011. For Stage2 subjects this meant the absence of active monthly visits during Dec 2010-Feb 2011.

That is, the study group was selected later. This is significant because it’s well known that malarial rates vary both seasonally and annually.^[3,4,5] Thus, the both active and control malaria study partipants must be chosen at the same time. The fact that they weren’t should invalidate the entire post-study, which includes their most significant results of 9 cases of malaria.

Study Funding

This study was funded by the vaccine’s manufacturer, BIKEN. The company was also directly involved in the study, including its design, conduct, and “logistical support”. Further, the following members of the research team had significant associations with the manufacturer:

• Toshihiro Horii (study leader): With BIKEN, a patent coholder for the vaccine
• Nirianne Marie Q. Palacpac: BIKEN employee (employed as BIKEN researcher during the trial)
• Nahoko Suzuki: BIKEN employee
• Takuya Okada: BIKEN employee
• Edward Ntege: received honorarium from BIKEN to perform the study
• Christopher Nsereko: received honorarium from BIKEN to perform the study
• Betty Balikagala: received honorarium from BIKEN to perform the study
• Bernard N. Kanoi: received honorarium from BIKEN to perform the study
• KT was named as formerly a BIKEN staff member. None of the authors listed has those initials.

Obviously, the majority of researchers are beholden to the manufacturer, and one is a coholder of the vaccine’s patent!

Study Flaws

Flaws in this study are amazing, leaving little reason to take it seriously. Add in the facts that the study was financed by the manufacture, BIKEN, which also was involved in its design, conduct, and logistical support, and that the majority of researchers—including one who’s a patent holder for the vaccine—are deep into BIKEN’s pockets, leads one to suspect that the study was set up to achieve a particular result.

It should, therefore, come as no surprise that the following flaws exist:

• Efficacy, the primary point being hyped, was not the primary end-point of the study.
• The primary end-point, adverse effects, were significant, likely resulting in a very large percentage of subject developing serious health effects. Though the authors of the study toss off a claim that they were not related to the vaccine, looking at the numbers makes that claim appear quite doubtful.
• The section of the trial that that utilized children as test subjects failed to test them for prior exposure to malaria. This seems highly questionable and may be part of the reason that the efficacy results seem so good.
• The other reason for apparently good efficacy results may be that the post-trial study used a control group that was chosen at a different time than the rest of the subjects. Looking at the results would tend to suggest that this is the most significant factor in apparently good efficacy.

The authors wrote:

Being a phase 1 trial, the study was not designed to detect efficacy.

Yet, that’s precisely the focus of reports on the trial! Why would this happen? The press acts primarily as a lapdog, rarely investigating the stories that they produce. Instead, the read press releases and blindly reports what they say. Who produces press releases? Those who hope to benefit from them.

In this case, the study was announced by the researchers at the Tokyo International Conference on African Development—and they initiated the focus on the study’s secondary results. The study’s leader, Toshihiro Horii, stated:

The vaccine’s effect is greater than those hitherto reported of any other antimalaria vaccines.

[and he further added that he hopes to put BK-SE36 to use:]

in five years after conducting a clinical trial on infants between zero and five, who account for the bulk of malaria deaths.

Of course, as a co-patent holder, he would hope to profit from the vaccine!

Sources:

1. Phase 1b Randomized Trial and Follow-Up Study in Uganda of the Blood-Stage Malaria Vaccine Candidate BK-SE36, PLoS ONE; Nirianne Marie Q. Palacpac, Edward Ntege, Adoke Yeka, Betty Balikagala, Nahoko Suzuki, Hiroki Shirai, Masanori Yagi, Kazuya Ito, Wakaba Fukushima, Yoshio Hirota, Christopher Nsereko, Takuya Okada, Bernard N. Kanoi, Toshihiro Horii; doi:10.1371/journal.pone.0064073.
2. Malaria – Symptoms
3. Annual variations in the number of malaria cases related to two different patterns of Anopheles darlingi transmission potential in the Maroni area of French Guiana; Malaria Journal; Florence Fouque^*, Pascal Gaborit, Romuald Carinci, Jean Issaly and Romain Girod; doi:10.1186/1475-2875-9-80.
4. Annual variations in the number of malaria cases related to two different patterns of Anopheles darlingi transmission potential in the Maroni area of French Guiana. BioMed Central; Florence Fouque, Pascal Gaborit, Romuald Carinci,² Jean Issaly, and Romain Gir; doi: 10.1186/1475-2875-9-80.
5. High annual and seasonal variations in malaria transmission by anophelines and vector species composition in Dielmo, a holoendemic area in Senegal; The American Journal of Tropical Medicine and Hygiene, 1997 Mar;56(3):247-53; Fontenille D, Lochouarn L, Diagne N, Sokhna C, Lemasson JJ, Diatta M, Konate L, Faye F, Rogier C, Trape JF;
6. New Japan malaria vaccine cuts infections ‘by 72%’

Tagged african malaria vaccine trial, african vaccine trial, big pharma, BK-SE, BK-SE36, junk science, malaria research flaws, malaria study flaws, malaria study hype, malaria vaccine, malaria vaccine efficacy, malaria vaccine gates foundation, malaria vaccine study, Phase 1b Randomized Trial and Follow-Up Study in Uganda of the Blood-Stage Malaria Vaccine Candidate BK-SE36, plos one, pseudo-science, pseudoscience, vaccine, vaccines