Commentary: Beneficial non-specific effects of measles vaccine: Fact or fiction?

ABSTRACT

A PLOS One review has claimed that randomized controlled trials (RCTs) show no beneficial nonspecific effects (NSEs) of measles vaccine (MV). Since this claim contradicts previous meta-analyses, we examined the contradictory views. RCTs of MV in low-income countries have mainly tested standard-titer-measles vaccine (STMV) vs high-titer-measles-vaccine (HTMV) (1980–90s) and two-dose vs one-dose of STMV (2000–10s). The PLOS One review claimed no NSEs in the RCTs of two-dose MV. The negative effect of HTMV was considered a specific effect due to an excessive vaccine dose. However, this does not explain why the negative effects only applied to females. Taking subsequent vaccinations into consideration in our reanalysis, one dose of STMV/HTMV versus control vaccine in the age interval 4–9 months, before controls received routine MV, was associated with a mortality ratio of 0.61 (0.37–0.99). After 9 months, randomization to STMV compared with HTMV-followed-by-a-non-live-vaccine had an MR of 0.72 (0.55–0.95), significantly better for females. Most RCTs in low-income countries experience interactions with vaccine campaigns and subsequent routine vaccinations. When these interactions are considered, the RCTs selected by the PLOS One review do show beneficial NSEs. NSEs are still critical factors to take into consideration in planning of vaccination policy.

Introduction

Thirty years ago, before randomized controlled trials (RCTs) of measles vaccine’s (MV) effect on mortality had been conducted, it was argued that MV had beneficial nonspecific effects (NSEs) because several epidemiological observations on MV could not be understood unless MV had beneficial NSEs.¹ These observations included: First, MV was associated with stronger reductions in mortality (30–86%) than the proportion of deaths attributed to measles infections. Excluding measles infection/deaths in the analysis contributed little to the reduction in mortality associated with MV. Second, major reductions in mortality after MV was supported by studies of the natural experiments comparing mortality before and after the introduction of MV; this has been strongly supported in subsequent studies (Table 1). Third, the effect appeared to be more beneficial for females than males; this has also been supported in subsequent studies.² Fourth, these effects were not merely a result of positive selection bias (the healthiest children having been vaccinated first), as a similar effect was not found for diphtheria-tetanus-pertussis (DTP) vaccine.

Table 1.

Community mortality before and after the introduction of measles vaccine.

Study site, Country	Age group (months)	Years compared	Mortality rate or risk (%) (deaths/person-years/N)		Mortality ratio of after vs before (95% CI)
			Before measles vaccination	After measles vaccination
Community studies
Kasongo, DR Congo19	7–21	1973–73 vs 1975–77	6.1 (21/346)	2.0 (6/392)	0.34 (0.15–0.76)
Bandafassi, Senegal21	9–60	1981–86 vs 1987–88	7.4 (345/4638)	3.7 (76/2026)	0.50 (0.39–0.65)
Bissau, Guinea-Bissau23	6–35	1979 vs 1980	12.7 (77/605)	4.7 (29/615)	0.37 (0.24–0.57)
Ballabgarh, India22	12–60	1985 vs 1987	6.9 (25/362)	2.9 (12/414)	0.42 (0.21–0.84)
Hospital study (case fatality in hospital)
South Africa24#	7–36	1977 vs 1978	17.1 (101/591)	7.8 (51/654)	0.46 (0.33–0.63)
Combined					0.45 (0.38–0.54)

Notes: # Nine measles cases (three deaths) are excluded from the 1977 statistics.

Abbreviations: CI, Confidence Interval.

A recent meta-analysis by Fournais at al. in PLOS One “found no support for beneficial non-specific effects of STMV (standard-titre-measles-vaccine), but linked HTMV (high-titre-measles-vaccine) to increased female mortality.”³ [STMV has a titer of ~5,000 plaque-forming units (pfu) whereas MV with higher titers had >40,000 pfu or >100,000 pfu.⁴] The negative effect of HTMV was labeled a specific effect of using too large a dose of vaccine virus. The authors include only randomized controlled trials (RCTs) in their review, since RCTs are said to represent the “highest level of evidence.”³

These conclusions contradict a WHO-commissioned meta-analysis conducted in 2014² and that Nature made the discovery of beneficial nonspecific effects (NSEs) of MV a milestone in vaccinology.⁵ Since the public perception of MV is critical we examined how the PLOS One paper reached the opposite conclusion.

MV is a WHO-recommended vaccine, so few ethical committees in low-income countries would approve RCTs comparing MV and placebo. RCTs have therefore only been conducted in special circumstances. The two main contexts have been RCTs comparing STMV with the new HTMV in the 1980–90s^4,6–9 and subsequent RCTs comparing an early two-dose versus a one-dose schedule with STMV.^10–13 The RCTs in Fournais et al.’s review stem precisely from these two situations as discussed below.

When analyzing NSEs, it is important to keep in mind that NSEs of a vaccine are not a response to a specific pathogen, but a modulation of the immune system which may enhance or reduce responses to subsequent unrelated pathogen exposures.^14,15 These modulations have been shown to be mediated via epigenetic reprogramming of innate immune cells.¹⁴ More specifically, for MV trained immunity may be induced via functional and metabolic reprogramming of γδ T-cells.¹⁶ The state of “trained innate immunity” induced by one vaccine can be modified by subsequent vaccinations. Hence, when assessing NSEs of a specific vaccine, the evaluation should be limited to the period until a new vaccine is received.¹⁵ This principle is particularly important in low-income countries where there are many other concurrent health interventions, which may affect children’s immune system.

We therefore examined how the PLOS One paper reached conclusions contradicting previous assessments, and whether the RCTs selected by Fournais et al. showed any indication of NSEs.

Material and methods

Though Fournais et al. examined RCTs of both mortality and morbidity, we have limited the presentation and discussion to data on mortality since all the original studies proposing NSEs focused on mortality. Mortality estimates are strongly affected when another routine or campaign vaccine is given after the initial trial vaccine. We have therefore censored for these vaccines where the information was available.

Based on previous reviews of MV,^2,3,15,17 we examine the data on the NSEs of MV, including RCTs, community trials, natural experiments and observational studies. The literature search for studies of MV has been described in these reviews^2,3,15,17 and we conducted no new searches specifically for this commentary.

The trials of HTMV included in the PLOS One review correspond to the studies previously included in a meta-analysis of HTMV.¹⁸ All RCTs randomized children at 4–6 months of age to HTMV or control vaccine; at 9 months the HTMV-recipients received a non-live control vaccine and controls received STMV.

The RCTs of STMV included three two-dose trials where children were randomly allocated to two doses of MV at 4 and 9 months of age vs no dose at 4 months and one dose of MV at 9 months of age.^10–12

Results

Origin of the nonspecific effect hypothesis for MV

Community trials

The concept was initially generated by studies in Guinea-Bissau, showing major declines in all-cause child mortality after the introduction of MV¹ and similar results in large community trials from DR Congo and Bangladesh.^19,20 In the large community trials from DR Congo and Bangladesh, some districts were allocated to MV and some to no MV. These community trials did not have the usual healthy vaccinee bias, common to observational studies, because districts were allocated to MV or no vaccine. The mortality ratio (MR) for MV versus unvaccinated children in the community trials was 0.29 (0.09–0.98) in DR Congo and 0.51 (0.42–0.62) in Bangladesh, for a combined MR of 0.50 (0.42–0.61).

Natural experiments

Natural experiments, where MV was introduced in a campaign and mortality was compared in the years before-and-after the campaign, contributed to the idea that MV had beneficial NSEs. In the four community studies from Senegal, DR Congo, India and Guinea-Bissau^19,21–23 and one hospital study from South Africa,²⁴ the MR for MV-year versus no-MV-year was 0.45 (0.38–0.54) (Table 1). There were no other interventions being introduced in the age group of MV recipients.

In another natural experiment, blood samples were collected from all children who received MV during one year in Bandim.²⁵ Samples were only analyzed two years later; during a short time window, no child had seroconverted having apparently received an inert MV. Outside this window, nearly all children seroconverted. Comparing the two groups of children, the MR for children receiving an active MV compared with an inert MV was 0.33 (0.11–0.97).

Observational studies

In 2014, WHO commissioned a review of the NSEs of Bacillus Calmette-Guérin (BCG), diphtheria-tetanus-pertussis (DTP) and MV. The analysis of MV was based on four RCTs showing a relative risk (RR) of mortality of 0.74 (0.51–1.07) and 18 observational studies indicating an RR of 0.51 (0.42–0.63) for MV versus no MV². The WHO review concluded that “receipt of BCG and MCV (measles-containing vaccine) reduce overall mortality by more than would be expected, though their effects on the diseases they prevent.”²

The PLOS One review

Fournais et al. identified eight papers representing five RCTs of HTMV and seven papers representing five RCTs of STMV investigating mortality as the primary outcome.³ Notably, Fournais et al. did not mention several RCTs from Nigeria^26,27 and Guinea-Bissau^28–30 included in previous systematic reviews of MV^1,2,17 . These RCTs had a combined MR of 0.75 (0.47–1.20) (Supplementary Table S1).

HTMV

Fournais et al. assessed the effect of HTMV from 4–6 months to 3–5 y of age, reporting that HTMV was associated with a mortality ratio (MR) of 1.22 (1.02–1.46), the negative effect being strongest for females (1.45 (1.06–1.99)).³ In their interpretation, this was likely due to a too high viral dose in the HTMV, i.e., not a negative NSE.³

STMV

The RCTs of STMV included three two-dose trials where children were randomly allocated to two doses of MV at 4 and 9 months at age vs no dose at 4 months and one dose of MV at 9 months of age.^10–12 The children were followed from inclusion to 3–5 y of age, with no censoring due to other vaccines. Two small trials^31,32 had incomparable designs and have not been further considered here. Though trial designs were similar, the three RCTs of two doses of STMV had very heterologous results, with the MRs for two-dose vs one-dose schedule ranging from 0.70 (0.52–0.94) to 1.38 (0.92–2.06) (p = .018). However, their meta-analysis of the RCTs of STMV gave an estimate of 1.00 (0.84–1.18).

Hence, they “found no support for beneficial non-specific effects of standard-titre-measles-vaccine.”

An analysis of the PLOS One selected RCTs taking other vaccines into account

Fournais et al. did not follow the principle of assessing the NSEs of a given vaccine until the next vaccine is given as recommended by the WHO-commissioned meta-analysis of the NSEs of MV². We have therefore reanalyzed the RCTs included in their review following this principle.^2,15

Due to similar design, it is possible to compare one MV (HTMV or STMV) with a control vaccine/placebo between 4–9 months of age, before MV is provided to the controls.²

Effects before 9 months of age

HTMV RCTs

In the RCTs, the HTMV groups compared with controls had an MR of 0.77 (0.49–1.21) from 4 to 9 months.¹⁸ If the analysis was censored for receipt of DTP, the MR for one dose of HTMV vs control was 0.20 (0.06–0.65).¹⁸ These estimates were unchanged if measles infections were censored in the analysis.¹⁸

Two-dose STMV RCTs

The MR for one-dose of MV versus 0-dose in an analysis of all three data sets¹³ was 0.88 (0.55–1.33) (Supplementary Table S2). Censoring for C-OPVs, the MR for one-dose vs 0-dose was 0.76 (0.44–1.30).

HTMV and STMV combined

In a meta-analysis of both types of measles vaccines, one dose of MV was associated with an MR of 0.82 (0.60–1.13). When censoring follow-up at receipt of unrelated vaccines (DTP or C-OPV) the combined MR became 0.61 (0.37–0.99).

Effects after 9 months of age

HTMV RCTs

From 9 months of age, the HTMV RCTs were also RCTs of STMV being compared with a non-live-control-vaccine-after-HTMV.^7,18 STMV had an MR of 0.72 (0.55–0.95) compared to the non-live vaccine (Table 2). The higher female mortality in the HTMV group was linked to HTMV-recipients receiving a non-live vaccine (DTP, IPV, or meningitis polysaccharide vaccine) at 9 months of age.^7,18 Supporting that this was NSEs, the beneficial effects of STMV were significantly different for females compared to males (p = .02) (Table 2).

Table 2.

RCTs of HTMV after the second vaccination at 9–10 months and until end of study.

Study	Non-live vaccine after HTMV	Age (months)	Mortality (deaths/person-years)		Mortality ratio
			STMV (controls)	Non-live vaccine after HTMV
Bissau EZ1 MT6	IPV	10–60	17/632.3	23/644.1	0.76 (0.40–1.41)
Bissau EZ2 MT4	IPV	10–48	5/134.3	9/134.0	0.55 (0.18–1.64)
Bissau EZ2 HT4	IPV	10–48	9/161.8	11/158.5	0.81 (0.33–1.96)
Gambia EZ HT7	IPV	10–36	0/134.7	3/137.2	0
Senegal Cohort 1–168	DTP-IPV+YF	10–60	23/844.0	54/1354.8	0.69 (0.42–1.12)
Senegal Cohort 17–248	DTP-IPV+YF	10–60	20/530.1	22/540.4	0.93 (0.51–1.69)
Sudan9	Meningitis	10–36	7/606.8	12/641.8	0.63 (0.25–1.59)
All trials					0.72 (0.55–0.95)
Females					0.53 (0.36–0.79)
Males					1.02 (0.68–1.52)

Abbreviations: DTP, Diphtheria-Tetanus-Pertussis. EZ, Edmonston-Zagreb. MT, Median-Titre. HT, High-Titer. IPV, Inactivated Polio Vaccine. HTMV, High Titer Measles Vaccine. STMV, Standard Titer Measles Vaccine. YF, Yellow Fever.

Two-dose STMV RCTs

The MR after 9 months of age in the three two-dose RCTs of STMV was 0.99 (0.79–1.25). However, if censored for C-OPV-after-enrollment, the MR for two-doses versus one-dose of STMV was 0.56 (0.34–0.90) after 9 months (Supplementary Table S2).¹³

Discussion

There are good ethical reasons that there are few RCTs of MV against placebo in low-income countries. Reviewing all available evidence, not only RCTs, may give a clearer picture of the MV non direct effects. The fact that a study is called a “randomised controlled trial” does not mean that it necessarily holds the “truth” if the context is not taken into consideration.³³ This is particularly so in low-income settings where there is likely to be numerous other interventions during the conduct of a trial. In other words, there is no point in pretending that an RCT solely examined the impact of MV versus placebo, if, during the conduct of the trial, both groups received campaigns with OPV (C-OPV), MV, or other routine vaccinations, which may have affected both randomization arms. It is worth emphasizing that when RCTs are impossible for ethical reasons, it may be possible to get plausible evidence for NSEs of a certain vaccine, for example, because its effects are markedly different for females and males, or because a campaign with the vaccine changes the result of other RCTs before and after the campaign.³⁴

The WHO-commissioned meta-analysis of NSEs of BCG, DTP and MV emphasized the until-the-next-vaccine-principle by only assessing NSEs until a new vaccine was provided, wherever information was available to censor for the new vaccines.² When measles cases/deaths were excluded from the analysis, the estimated RR hardly changed,¹ so prevention of measles infection explained little of the overall effect on survival.

Fournais et al. screened 4315 articles, but found few RCTs on the NSEs of MV. Their dismissal of all NSEs for MV is built on limiting their review to a subset of existing RCTs,³ without attempt to account for the totality of data. Furthermore, the reported outcomes of the studies may be affected by the following limitations:

First, they claim that the increased mortality associated with HTMV is due to a specific effect of an excessive dose of vaccine virus. This is not possible for several reasons: First, from 4 to 9 months of age, as described above, the HTMV-recipients had lower mortality than the MV-unvaccinated control group.¹⁸ Second, the negative effect from 9 months of age affected only females, which is common for NSEs,¹⁵ whereas it is biologically unlikely that females should suffer significantly more than males from a 10-fold higher vaccine dose. Third, HTMV-recipients, who did not receive DTP after HTMV, did not have excess mortality.⁷ So, HTMV per se did not induce higher mortality, the subsequent non-live vaccine at 9 months did.

The second claim is that the meta-analysis of the two-dose STMV trials showed no beneficial NSEs because the mortality ratio for the two-dose vs one-dose group was 1.0. As discussed above, focusing exclusively on RCTs may not allow for a complete interpretation of data. The Cochrane handbook suggests that non-randomized studies should be included where RCTs are scarce.³⁵ Fournais et al. did not include all RCTs (Supplementary Table S1). Importantly, the Fournais-paper did not take into consideration that NSEs interact with other interventions. As documented by Hernán and colleagues,³⁶ post-randomization confounding and selection bias emerge in RCTs. Following children for years, beyond the reception of other vaccines as done in the Fournais et al. analysis³ will distort the comparison: the RCTs are no longer comparing MV versus control vaccine but cocktails of different vaccines and interactions in both groups.

Some problems in the Fournais-paper become clear when analyses adhere to the principles for studying NSEs as done in the previous WHO-sponsored meta-analysis of NSEs.^2,15 In the RCTs that were dismissed as showing no evidence for NSEs by Fournais et al., there was in fact significant beneficial NSEs of MV: one dose of HTMV or STMV compared with no MV had beneficial effects between 4 and 9 months of age, when unrelated vaccines were controlled in the analysis. Furthermore, when the control group randomized to receiving STMV at 9 months was compared with children receiving a non-live-vaccine-after-HTMV, STMV had beneficial NSEs which were particularly beneficial for females.¹⁸

Conclusions

The implications of these analytical oversights are not trivial: The dismissal of NSEs could be problematic if it leads to the withdrawal of MV once measles virus has been eradicated. As MV has beneficial NSEs with current knowledge, removing the vaccine would likely increase child mortality in low-income countries.³⁷

The scientific and social focus should be on exploring how the beneficial NSEs of MVs can be used to reduce child mortality, and possibly also adult mortality.

Biography

Peter Aaby, Trained as a social anthropologist, I built a large health and demographic surveillance system in Guinea-Bissau. In 1978, under-5 child mortality was 500/1000. The high case fatality in measles infection (21%) was not due to malnutrition but to intensive exposure as a secondary case within the family. We introduced measles vaccine (MV) in 1979. The first campaign reduced mortality to one-third, an effect not explained by prevention of measles. These non-specific effects (NSEs) of MV led to several discoveries contradicting the specific-disease-specific-vaccine paradigm. So far, the live vaccines including BCG, MV, OPV, and vaccinia have been found to have strong beneficial NSEs. Unfortunately, non-live vaccine may misdirect the immune system leading to higher mortality, particularly for girls. This was found for five non-live vaccines including DTP, IPV, HBV, Penta, and RTS,S malaria vaccine. Sequence of vaccinations, sex-differential effects, boosting and maternal priming are very important features of the NSEs of vaccines. Pursuing this paradigm can lead to major reductions in child mortality in low-income countries. The NSE paradigm is also relevant for adult vaccinations and adult mortality. During the COVID-19 pandemic several trials of BCG vs placebo showed BCG to be associated with major reductions in adult mortality.

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The study was based exclusively on published sources and is therefore available for all.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2025.2596420.

Ethics approval

No ethical approval was necessary.

Transparency

The lead author (the guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported and that no important aspects of the study have been omitted.

Abbreviations

CI Confidence Interval

C-OPV Campaign Oral Polio Vaccine

MRR Mortality Rate Ratio

MV Measles Vaccine

RCT Randomised Controlled Trial